Pyrimidinones as factor xia inhibitors

ABSTRACT

The present invention provides compounds of Formula (I): 
     
       
         
         
             
             
         
       
     
     or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, wherein all the variables are as defined herein. These compounds are selective factor XIa inhibitors or dual inhibitors of FXIa and plasma kallikrein. This invention also relates to pharmaceutical compositions comprising these compounds and methods of treating thromboembolic and/or inflammatory disorders using the same.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.15/221,142, filed Jul. 27, 2016 which is a continuation of U.S.application Ser. No. 14/872,546, filed Oct. 1, 2015, now U.S. Pat. No.9,453,018, which is entitled to priority pursuant to 35 U.S.C. § 119(e)to U.S. provisional patent application Nos. 62/058,316 and 62/058,293,both filed on Oct. 1, 2014, which are incorporated herein in theirentireties.

FIELD OF THE INVENTION

The present invention relates generally to novel macrocyclic compounds,and their analogues thereof, which are factor XIa inhibitors or dualinhibitors of factor XIa and plasma kallikrein, compositions containingthem, and methods of using them, for example, for the treatment orprophylaxis of thromboembolic disorders, or for the treatment of retinalvascular permeability associated with diabetic retinopathy and diabeticmacular edema.

BACKGROUND OF THE INVENTION

Thromboembolic diseases remain the leading cause of death in developedcountries despite the availability of anticoagulants such as warfarin(COUMADIN®), heparin, low molecular weight heparins (LMWH), andsynthetic pentasaccharides and antiplatelet agents such as aspirin andclopidogrel (PLAVIX®). The oral anticoagulant warfarin, inhibits thepost-translational maturation of coagulation factors VII, IX, X andprothrombin, and has proven effective in both venous and arterialthrombosis. However, its usage is limited due to its narrow therapeuticindex, slow onset of therapeutic effect, numerous dietary and druginteractions, and a need for monitoring and dose adjustment. Thusdiscovering and developing safe and efficacious oral anticoagulants forthe prevention and treatment of a wide range of thromboembolic disordershas become increasingly important.

One approach is to inhibit thrombin generation by targeting theinhibition of coagulation factor XIa (FXIa). Factor XIa is a plasmaserine protease involved in the regulation of blood coagulation, whichis initiated in vivo by the binding of tissue factor (TF) to factor VII(FVII) to generate factor VIIa (FVIIa). The resulting TF:FVIIa complexactivates factor IX (FIX) and factor X (FX) that leads to the productionof factor Xa (FXa). The generated FXa catalyzes the transformation ofprothrombin into small amounts of thrombin before this pathway is shutdown by tissue factor pathway inhibitor (TFPI). The process ofcoagulation is then further propagated via the feedback activation ofFactors V, VIII and XI by catalytic amounts of thrombin. (Gailani, D. etal., Arterioscler. Thromb. Vasc. Biol., 27:2507-2513 (2007).) Theresulting burst of thrombin converts fibrinogen to fibrin thatpolymerizes to form the structural framework of a blood clot, andactivates platelets, which are a key cellular component of coagulation(Hoffman, M., Blood Reviews, 17:S1-S5 (2003)). Therefore, factor XIaplays a key role in propagating this amplification loop and is thus anattractive target for anti-thrombotic therapy.

An alternative way of initiation of coagulation is operative when bloodis exposed to artificial surfaces. This process is also termed contactactivation. Surface absorption of factor XII leads to a conformationalchange in the factor XII molecule, thereby facilitating activation toproteolytic active factor XII molecules (factor XIIa and factor XIIf).Factor XIIa (or XIIf) has a number of target proteins, including plasmaprekallikrein and factor XI.

Plasma prekallikrein is a zymogen of a trypsin-like serine protease andis present in plasma at 35 to 50 μg/mL. The gene structure is similar tothat of factor XI. Overall, the amino acid sequence of plasma kallikreinhas 58% homology to factor XI. Plasma kallikrein is thought to play arole in a number of inflammatory disorders. The major inhibitor ofplasma kallikrein is the serpin C1 esterase inhibitor. Patients whopresent with a genetic deficiency in C1 esterase inhibitor suffer fromhereditary angioedema (HAE) which results in intermittent swelling offace, hands, throat, gastrointestinal tract and genitals. Blistersformed during acute episodes contain high levels of plasma kallikreinwhich cleaves high molecular weight kininogen liberating bradykininleading to increased vascular permeability. Treatment with a largeprotein plasma kallikrein inhibitor has been shown to effectively treatHAE by preventing the release of bradykinin which causes increasedvascular permeability (Lehmann, A., “Ecallantide (DX-88), a plasmakallikrein inhibitor for the treatment of hereditary angioedema and theprevention of blood loss in on-pump cardiothoracic surgery”, ExpertOpin. Biol. Ther., 8:1187-1199 (2008)).

The plasma kallikrein-kinin system is abnormally abundant in patientswith advanced diabetic macular edema. It has been recently publishedthat plasma kallikrein contributes to retinal vascular dysfunctions indiabetic rats (Clermont, A. et al., “Plasma kallikrein mediates retinalvascular dysfunction and induces retinal thickening in diabetic rats”,Diabetes, 60:1590-1598 (2011)). Furthermore, administration of theplasma kallikrein inhibitor ASP-440 ameliorated both retinal vascularpermeability and retinal blood flow abnormalities in diabetic rats.Therefore, a plasma kallikrein inhibitor should have utility as atreatment to reduce retinal vascular permeability associated withdiabetic retinopathy and diabetic macular edema. Other complications ofdiabetes such as cerebral hemorrhage, nephropathy, cardiomyopathy andneuropathy, all of which have associations with plasma kallikrein mayalso be considered as targets for a plasma kallikrein inhibitor.

To date, no small molecule synthetic plasma kallikrein inhibitor hasbeen approved for medical use. The large protein plasma kallikreininhibitors present risks of anaphylactic reactions, as has been reportedfor Ecallantide. Thus there remains a need for compounds that inhibitplasma kallikrein, that do not induce anaphylaxis and that are orallyavailable. Furthermore, the molecules in the known art feature a highlypolar and ionizable guanidine or amidine functionality. It is well knownthat such functionalities may be limiting to gut permeability andtherefore to oral availability.

SUMMARY OF THE INVENTION

The present invention provides novel macrocyclic compounds, theiranalogues, including stereoisomers, tautomers, pharmaceuticallyacceptable salts, or solvates thereof, which are useful as selectivefactor XIa inhibitors or dual inhibitors of factor XIa and plasmakallikrein.

The present invention also provides processes and intermediates formaking the compounds of the present invention.

The present invention also provides pharmaceutical compositionscomprising a pharmaceutically acceptable carrier and at least one of thecompounds of the present invention or stereoisomers, tautomers,pharmaceutically acceptable salts, or solvates thereof.

The compounds of the invention may be used in the treatment and/orprophylaxis of thromboembolic disorders.

The compounds of the invention may be used in the treatment of retinalvascular permeability associated with diabetic retinopathy and diabeticmacular edema.

The compounds of the present invention may be used in therapy.

The compounds of the present invention may be used for the manufactureof a medicament for the treatment and/or prophylaxis of a thromboembolicdisorder.

The compounds of the invention can be used alone, in combination withother compounds of the present invention, or in combination with one ormore, preferably one to two other agent(s).

These and other features of the invention will be set forth in expandedform as the disclosure continues.

DETAILED DESCRIPTION OF THE INVENTION I. Compounds of the Invention

In one aspect, the present invention provides, inter alia, compounds ofFormula (I):

or stereoisomers, tautomers, pharmaceutically acceptable salts,solvates, or prodrugs thereof, wherein:

ring A is independently selected from 6-membered aryl and 5- to6-membered heterocyclyl, wherein said aryl and heterocyclyl areoptionally substituted with, where valence allows, one or more R⁴;

ring B is 5- to 10-membered heterocyclyl optionally substituted with,where valence allows, one or more R³ or 5- to 10-membered heterocyclylcomprising carbon atoms and 1-4 heteroatoms selected from N, NR^(3c), O,and S(O)_(p) and optionally substituted with, where valence allows, oneor more R³;

G¹ is independently selected from C₃₋₁₀ carbocyclyl and 5- to10-membered heterocyclyl, wherein said carbocyclyl and heterocyclyl areoptionally substituted with, where valence allows, one or more R⁸;

X is independently selected from C₄₋₈ alkylene and C₄₋₈ alkenylene,wherein said alkylene and alkenylene are substituted with R¹ and R²;alternatively one or more of the carbon atoms of said alkylene andalkenylene may be replaced by O, C═O, S(═O)_(p), S(═O)_(p)NH, and NR¹⁵;

Y is independently selected from —CR¹³NH—, —NHC(═O)—, —C(═O)NH—,—S(═O)_(p)NH—, —NHS(═O)_(p)—, and C₁₋₂ alkylene;

R¹ and R² are independently selected from H, D, halogen, haloalkyl, C₁₋₆alkyl (optionally substituted with R⁶), hydroxyl, and alkoxy optionallysubstituted with R⁶, and C₃₋₆ cycloalkyl optionally substituted with R⁶;optionally, when R¹ and R² are attached to the same carbon atom,together they form an oxo group or C₃₋₆ cycloalkyl; optionally, when R¹and R² are attached to carbon atoms adjacent to each other, togetherthey form a bond or carbocyclyl; optionally, R¹ and R¹⁵ or R² and R¹⁵taken together form a ring;

R³ is independently selected from H, NO₂, ═O, halogen, haloalkyl, C₁₋₄alkyl (optionally substituted with R⁶), C₂₋₄ alkenyl (optionallysubstituted with R⁶), C₂₋₄ alkynyl (optionally substituted with R⁶), CN,—(CH₂)_(n)—OR⁵, —(CH₂)_(n)—NR⁵R⁵, —(CH₂)_(n)—C(═O)R⁵,—(CH₂)_(n)—C(═O)OR⁵, —(CH₂)_(n)—NR⁹C(═O)OR⁵, —(CH₂)_(n)—NR⁹C(═O)R⁵,—(CH₂)_(n)—NR⁹C(N—CN)NHR⁵, —(CH₂)_(n)—NR⁹C(NH)NHR⁵,—(CH₂)_(n)—N═CR⁹NR⁵R⁵, —(CH₂)_(n)—NR⁹C(═O)NR⁵R⁵, —(CH₂)_(n)—C(═O)NR⁵R⁵,—(CH₂)_(n)—NR⁹C(═S)NR⁹C(═O)R⁵, —(CH₂)_(n)—S(═O)_(p)R⁵,—(CH₂)_(n)—S(═O)_(p)NR⁵R⁵, —(CH₂)_(n)—NR⁹S(═O)_(p)NR⁵R⁵,—(CH₂)_(n)—NR⁹S(═O)_(p)R⁵, —(CH₂)_(n)—C₃₋₁₀ carbocyclyl and—(CH₂)_(n)-4- to 10-membered heterocyclyl, wherein said carbocyclyl andheterocyclyl are optionally substituted with R⁶; optionally, twoadjacent R³ groups on the heterocyclyl may form a ring optionallysubstituted with R⁶;

R^(3c) is independently selected from H, haloalkyl, C₁₋₄ alkyl(optionally substituted with R⁶), —(CH₂)₁₋₂—OH, C(═O)C₁₋₄ alkyl,—(CH₂)₀₋₂—C(═O)OH, —C(═O)OC₁₋₄ alkyl, S(═O)_(p)C₁₋₆ alkyl,—(CH₂)_(n)—C₃₋₁₀ carbocyclyl and —(CH₂)_(n)-4- to 10-memberedheterocyclyl, wherein said carbocyclyl and heterocyclyl are optionallysubstituted with R⁶;

R⁴ is independently selected from H, OH, NH₂, halogen, CN, C₁₋₄ alkyl,C₁₋₄ haloalkyl, C₁₋₄ alkoxy, —CH₂OH, —C(═O)OH, —CH₂C(═O)OH, —CO₂(C₁₋₄alkyl), —C(═O)NH₂, —C(═O)NH(C₁₋₄ alkyl), —C(═O)N(C₁₋₄ alkyl)₂,—S(═O)₂C₁₋₄ alkyl, —S(═O)₂NH₂, C₃₋₆ cycloalkyl, aryl, and 5- to6-membered heterocyclyl, wherein said cycloalkyl, aryl and heterocyclylare optionally substituted with R⁶;

R⁵ is independently selected from H, C₁₋₄ alkyl (optionally substitutedwith halogen, hydroxyl, alkoxy, carboxy, hydroxycarbonyl,alkoxycarbonyl, amino, substituted amino), —(CH₂)_(n)—C₃₋₁₀ carbocyclyland —(CH₂)_(n)-4- to 10-membered heterocyclyl, wherein said carbocyclyland heterocyclyl are optionally substituted with R⁶; alternatively, R⁵and R⁵ together with the nitrogen atom to which they are both attachedform a heterocyclic ring optionally substituted with R⁶;

R⁶ is independently selected from H, —(CH₂)_(n)—OH, ═O, —(CH₂)_(n)NH₂,—(CH₂)_(n)CN, halogen, C₁₋₆ alkyl, —(CH₂)_(n)—C(═O)OH,—(CH₂)_(n)—C(═O)NH₂, —(CH₂)_(n)—C(═O)OC₁₋₄ alkyl, —(CH₂)_(n)—OC₁₋₄alkyl, —(CH₂)_(n)—C₃₋₁₀ carbocyclyl, —(CH₂)_(n)-4- to 10-memberedheterocyclyl, and —O-4- to 10-membered heterocyclyl, wherein saidcarbocyclyl and heterocyclyl are optionally substituted with R¹⁰;

R⁷ is independently selected from H, hydroxyl, alkoxy, halogen, amino,C₁₋₃haloalkyl, and C₁₋₃ alkyl;

R⁸ is independently selected from H, halogen, —(CH₂)_(n)CN, C₁₋₆ alkyl,amino, aminoalkyl, haloalkyl, hydroxyl, alkoxy, haloalkoxy,alkylcarbonyl, carboxyl, carboxyl ester, amide, haloalkylaminocarbonyl,arylalkylaminocarbonyl, haloalkylaminocarbonyl, alkoxycarbonylamino,haloalkylcarbonylamino, arylamino, heteroarylamino, arylalkylcarbonyl,aryloxy, heteroaryloxy, alkylthio, alkylsulfonyl, arylsulfonyl,heteroarylsulfonyl, sulfonamide, —(CH₂)_(n)-aryl, —(CH₂)_(n)—C₃₋₆cycloalkyl, and —(CH₂)_(n)-4- to 12-membered heterocyclyl, wherein saidaryl, cycloalkyl, and heterocyclyl are optionally substituted with R¹⁰;

alternatively, two adjacent R⁸ groups taken together form a heterocyclicring optionally substituted with R¹⁰;

R⁹ is H or C₁₋₆ alkyl;

R¹⁰ is independently selected from H, C₁₋₆ alkyl (optionally substitutedwith R¹¹), C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl (optionally substituted withR¹¹), —(CH₂)_(n)—C₃₋₆ cycloalkyl (optionally substituted with R¹¹),—(CH₂)_(n)—O-4- to 10-membered heterocyclyl (optionally substituted withR¹¹), halogen, —(CH₂)_(n)CN, NO₂, ═O, C(═O)NR¹²R¹², —(CH₂)_(n)C(═O)OR¹²,Si(C₁₋₄ alkyl)₃, —(CH₂)_(n)—OR¹², —(CH₂)_(n)—NR¹²R¹², —S(═O)_(p)C₁₋₆alkyl, NR¹²S(═O)_(p)C₁₋₆ alkyl, S(═O)_(p)NR¹²R¹², and C(═NOH)NH₂;

R¹¹, at each occurrence, is independently selected from H, halogen, C₁₋₅alkyl, —(CH₂)_(n)—OH, C₃₋₆ cycloalkyl, phenyl, and heterocyclyl;

R¹², at each occurrence, is independently selected from H, C₁₋₅ alkyloptionally substituted with R¹¹, C₃₋₆ cycloalkyl, phenyl, andheterocyclyl, or R¹² and R¹² together with the nitrogen atom to whichthey are both attached form a heterocyclic ring optionally substitutedwith C₁₋₄alkyl;

R¹³ is, independently at each occurrence, selected from H, C₁₋₄haloalkyl, C₁₋₄ alkyl, C(═O)OH, C(═O)O(C₁₋₄ alkyl), C(═O)O(CH₂)₂O(C₁₋₄alkyl), C(═O)O(C₁₋₄ haloalkyl), CH₂C(═O)OH, CH₂C(═O)O(C₁₋₄ alkyl),C(═O)NH₂, C(═O)NH(C₁₋₄ alkyl), C(═O)N(C₁₋₄ alkyl)₂, and —C(═O)NH(C₁₋₄alkoxy);

R¹⁵ is H or C₁₋₆ alkyl;

n, at each occurrence, is an integer independently selected from 0, 1,2, 3, and 4; and

p, at each occurrence, is an integer independently selected from 0, 1,and 2.

In another aspect, the present invention provides compounds of Formula(I) or stereoisomers, tautomers, pharmaceutically acceptable salts,solvates, or prodrugs thereof, wherein:

ring A is independently selected from a 6-membered aryl and a 5- to6-membered heterocycle, wherein said aryl and heterocycle are optionallysubstituted with, where valence allows, one or more R⁴;

ring B is a 5- to 10-membered heterocycle optionally substituted with,where valence allows, one or more R³;

G¹ is independently selected from a C₃₋₁₀ carbocycle and a 5- to10-membered heterocycle, wherein said carbocycle and heterocycle areoptionally substituted with, where valence allows, one or more R⁸;

X is independently selected from C₄₋₈ alkylene and C₄₋₈ alkenylene,wherein said alkylene and alkenylene are substituted with R¹ and R²;alternatively one or more of the carbon atoms of said alkylene andalkenylene may be replaced by O, C═O, S(═O)_(p), S(═O)_(p)NH, NH, andN(C₁₋₄ alkyl);

Y is independently selected from —CR¹³NH—, —NHC(═O)—, —C(═O)NH—,—S(═O)_(p)NH—, —NHS(═O)_(p)—, and C₁₋₂ alkylene;

R¹ and R² are independently selected from H, halogen, haloalkyl, C₁₋₆alkyl (optionally substituted with R⁶), hydroxyl, and alkoxy (optionallysubstituted with R⁶), and C₃₋₆ cycloalkyl optionally substituted withR⁶; optionally, when R¹ and R² are attached to the same carbon atom,together they form an oxo group or C₃₋₆ cycloalkyl; optionally, when R¹and R² are attached to carbon atoms adjacent to each other, togetherthey form a bond or a carbocycle;

R³ is independently selected from H, NO₂, ═O, halogen, haloalkyl, C₁₋₄alkyl (optionally substituted with R⁶), C₂₋₄ alkenyl (optionallysubstituted with R⁶), C₂₋₄ alkynyl (optionally substituted with R⁶), CN,—(CH₂)_(n)—OR⁵, —(CH₂)_(n)—NR⁵R⁵, —(CH₂)_(n)—C(═O)R⁵,—(CH₂)_(n)—C(═O)OR⁵, —(CH₂)_(n)—NR⁹C(═O)OR⁵, —(CH₂)_(n)—NR⁹C(═O)R⁵,—(CH₂)_(n)—NR⁹C(N—CN)NHR⁵, —(CH₂)_(n)—NR⁹C(NH)NHR⁵,—(CH₂)_(n)—N═CR⁹NR⁵R⁵, —(CH₂)_(n)—NR⁹C(═O)NR⁵R⁵, —(CH₂)_(n)—C(═O)NR⁵R⁵,—(CH₂)_(n)—NR⁹C(═S)NR⁹C(═O)R⁵, —(CH₂)_(n)—S(═O)_(p)C₁₋₆ alkyl optionallysubstituted with R¹¹, —(CH₂)_(n)—S(═O)_(p)NR⁵R⁵,—(CH₂)_(n)—NR⁹S(═O)_(p)NR⁵R⁵, —(CH₂)_(n)—NR⁹S(═O)_(p)C₁₋₆ alkyloptionally substituted with R¹¹, —(CH₂)_(n)—C₃₋₁₀ carbocycle and—(CH₂)_(n)-4- to 10-membered heterocycle, wherein said carbocycle andheterocycle are optionally substituted with R⁶; optionally, two adjacentR³ groups on the carbocycle and heterocycle may form a ring optionallysubstituted with R⁶;

R⁴ is independently selected from H, OH, NH₂, halogen, CN, C₁₋₄ alkyl,C₁₋₄ haloalkyl, C₁₋₄ alkoxy, —CH₂OH, —C(═O)OH, —CH₂C(═O)OH, —CO₂(C₁₋₄alkyl), —C(═O)NH₂, —C(═O)NH(C₁₋₄ alkyl), —C(═O)N(C₁₋₄ alkyl)₂,—S(═O)₂C₁₋₄ alkyl, S(═O)₂NH₂, C₃₋₆ cycloalkyl, aryl, and 5- to6-membered heterocycle, wherein said cycloalkyl, aryl and heterocycleare optionally substituted with R⁶;

R⁵ is independently selected from H, C₁₋₄ alkyl (optionally substitutedwith halogen, hydroxyl, alkoxy, carboxy, alkoxycarbonyl, amino,substituted amino), —(CH₂)_(n)—C₃₋₁₀ carbocycle and —(CH₂)_(n)-4- to10-membered heterocycle, wherein said carbocycle and heterocycle areoptionally substituted with R⁶; alternatively, R⁵ and R⁵ together withthe nitrogen atom to which they are both attached form a heterocyclicring optionally substituted with R⁶;

R⁶ is independently selected from H, —(CH₂)_(n)—OH, ═O, —(CH₂)_(n)NH₂,—(CH₂)_(n)CN, halogen, C₁₋₆ alkyl, —(CH₂)_(n)—C(═O)OH,—(CH₂)_(n)—C(═O)OC₁₋₄ alkyl, —(CH₂)_(n)—OC₁₋₄ alkyl, —(CH₂)_(n)—C₃₋₁₀carbocycle, —(CH₂)_(n)-4- to 10-membered heterocycle, and —O-4- to10-membered heterocycle, wherein said carbocycle and heterocycle areoptionally substituted with R¹⁰;

R⁷ is independently selected from H, hydroxyl, alkoxy, halogen, amino,and C₁₋₃ alkyl;

R⁸ is independently selected from H, halogen, CN, NH₂, C₁₋₆ alkyl,haloalkyl, haloalkylcarbonylamine, alkylcarbonyl, hydroxyl, alkoxy,haloalkoxy, —(CH₂)_(n)-aryl, —(CH₂)_(n)—C₃₋₆ cycloalkyl, and—(CH₂)_(n)-4- to 6-membered heterocycle, wherein said aryl, cycloalkyl,and heterocycle are optionally substituted with R¹⁰;

alternatively, two adjacent R⁸ groups form a heterocyclic ringoptionally substituted with R¹⁰;

R⁹ is H or C₁₋₆ alkyl;

R¹⁰ is independently selected from H, C₁₋₆ alkyl (optionally substitutedwith R¹¹), C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, —(CH₂)_(n)—C₃₋₆ cycloalkyl(optionally substituted with R¹¹), —(CH₂)_(n)—O-4- to 10-memberedheterocycle (optionally substituted with R¹¹), halogen, CN, NO₂, ═O,C(═O)NR¹²R¹², C(═O)OH, Si(C₁₋₄ alkyl)₃, —(CH₂)_(n)—OR¹²,—(CH₂)_(n)—NR¹²R¹², and C(═NOH)NH₂;

R¹¹, at each occurrence, is independently selected from H, halogen, C₁₋₅alkyl, —(CH₂)_(n)—OH, C₃₋₆ cycloalkyl, phenyl, and heterocycle;

R¹², at each occurrence, is independently selected from H, C₁₋₅ alkyl,C₃₋₆ cycloalkyl, phenyl, and heterocycle, or R¹² and R¹² together withthe nitrogen atom to which they are both attached form a heterocyclicring optionally substituted with C₁₋₄alkyl;

R¹³ is, independently at each occurrence, selected from H, halogen, C₁₋₄haloalkyl, CO₂H, CO₂(C₁₋₄ alkyl), CO₂(CH₂)₂O(C₁₋₄ alkyl), CO₂(C₁₋₄haloalkyl), CO₂(CH₂)₂SO₂(C₁₋₄ alkyl), CH₂CO₂H, CH₂CO₂(C₁₋₄ alkyl),CONH₂, CONH(C₁₋₄ alkyl), CON(C₁₋₄ alkyl)₂, —CONH(C₁₋₄ alkoxy),—CO₂(CH₂)₂O(C₁₋₄ alkyl), —CO₂(CH₂)₂N(C₁₋₄ alkyl)₂, —CONH(CH₂)₂O(C₁₋₄alkyl), —CONH(CH₂)₂N(C₁₋₄ alkyl)₂, —CON(C₁₋₄ alkyl)(CH₂)₂O(C₁₋₄ alkyl),—CON(C₁₋₄ alkyl)(CH₂)₂N(C₁₋₄ alkyl)₂, C₁₋₄ alkyl, —CONHBn, —CONH(OBn),—(CO)₀₋₁(CH₂)₀₋₃—C₃₋₆ carbocycle, and—(CH₂)₀₋₁—(CO)₀₋₁—(V)₀₋₁—(CH₂)₀₋₂-(4- to 6-membered heterocyclecomprising carbon atoms and 1-4 heteroatoms selected from N, NH, N(C₁₋₄alkyl), O, and S(O)_(p)), wherein said carbocycle and heterocycle aresubstituted with 0-2 R¹⁴;

R¹⁴ is, independently at each occurrence, selected from the groupconsisting of: halogen, OH, CHF₂, CF₃, C₁₋₄ alkoxy, CH₂OH, CO₂H,CO₂(C₁₋₄ alkyl), CONH₂, and C₁₋₄ alkyl;

V is independently selected from O, NH and N(C₁₋₄ alkyl);

n, at each occurrence, is an integer independently selected from 0, 1,2, 3, and 4; and

p, at each occurrence, is an integer independently selected from 0, 1,and 2.

In another aspect, the present invention provides compounds of Formula(I) or stereoisomers, tautomers, pharmaceutically acceptable salts,solvates, or prodrugs thereof, wherein:

ring A is independently selected from a 6-membered aryl and a 5- to6-membered heterocycle, wherein said aryl and heterocycle are optionallysubstituted with, where valence allows, one or more R⁴;

ring B is a 5- to 10-membered heterocycle optionally substituted with,where valence allows, one or more R³;

G¹ is independently selected from a C₃₋₁₀ carbocycle and a 5- to10-membered heterocycle, wherein said carbocycle and heterocycle areoptionally substituted with, where valence allows, one or more R⁸;

X is independently selected from C₄₋₈ alkylene and C₄₋₈ alkenylene,wherein said alkylene and alkenylene are substituted with R¹ and R²;alternatively one or more of the carbon atoms of said alkylene andalkenylene may be replaced by O, C═O, S(O)_(p), S(O)_(p)NH, NH, andN(C₁₋₄ alkyl);

Y is independently selected from —NH—C(O)— and —C(O)—NH—;

R¹ and R² are independently selected from H, halogen, haloalkyl, C₁₋₆alkyl (optionally substituted with R⁶), hydroxyl, and alkoxy (optionallysubstituted with R⁶), and C₃₋₆ cycloalkyl optionally substituted withR⁶; optionally, when R¹ and R² are attached to the same carbon atom,together they form an oxo group or C₃₋₆cycloalkyl; optionally, when R¹and R² are attached to carbon atoms adjacent to each other, togetherthey form a bond or a carbocycle;

R³ is independently selected from H, NO₂, ═O, halogen, haloalkyl,C₁₋₄alkyl (optionally substituted with R⁶), C₂₋₄alkenyl (optionallysubstituted with R⁶), C₂₋₄alkynyl (optionally substituted with R⁶), CN,—(CH₂)_(n)—OR⁵, —(CH₂)_(n)—NR⁵R⁵, —(CH₂)_(n)—C(O)OR⁵,—(CH₂)_(n)—NR⁹C(O)OR⁵, —(CH₂)_(n)—NR⁹C(O)R⁵, —(CH₂)_(n)—NR⁹C(N—CN)NHR⁵,—(CH₂)_(n)—NR⁹C(NH)NHR⁵, —(CH₂)_(n)—N═CR⁹NR⁵R⁵, —(CH₂)_(n)—NR⁹C(O)NR⁵R⁵,—(CH₂)_(n)—C(O)NR⁵R⁵, —(CH₂)_(n)—NR⁹C(S)NR⁹C(O)R⁵,—(CH₂)_(n)—S(O)_(p)R¹², —(CH₂)_(n)—S(O)_(p)NR⁵R⁵,—(CH₂)_(n)—NR⁹S(O)_(p)NR⁵R⁵, —(CH₂)_(n)—NR⁹S(O)_(p)R¹², —(CH₂)_(n)—C₃₋₁₀carbocycle and —(CH₂)_(n)-4- to 10-membered heterocycle, wherein saidcarbocycle and heterocycle are optionally substituted with R⁶;optionally, two adjacent R³ groups on the carbocycle and heterocycle mayform a ring optionally substituted with R⁶;

R⁴ is independently selected from H, OH, NH₂, halogen, CN, C₁₋₄ alkyl,C₁₋₄ haloalkyl, C₁₋₄ alkoxy, —CH₂OH, —CO₂H, —CH₂CO₂H, —CO₂(C₁₋₄ alkyl),—C(O)NH₂, —C(O)NH(C₁₋₄ alkyl), —C(O)N(C₁₋₄ alkyl)₂, S(O)₂NH₂, C₃₋₆cycloalkyl, aryl, and 5- to 6-membered heterocycle, wherein saidcycloalkyl, aryl and heterocycle are optionally substituted with R⁶;

R⁵ is independently selected from H, C₁₋₄ alkyl (optionally substitutedwith halogen, hydroxyl, alkoxy, carboxy, alkoxycarbonyl, amino,substituted amino), —(CH₂)_(n)—C₃₋₁₀ carbocycle and —(CH₂)_(n)-4- to10-membered heterocycle, wherein said carbocycle and heterocycle areoptionally substituted with R⁶; alternatively, R⁵ and R⁵ together withthe nitrogen atom to which they are both attached form a heterocyclicring optionally substituted with R⁶;

R⁶ is independently selected from H, —(CH₂)_(n)—OH, ═O, —(CH₂)_(n)NH₂,—(CH₂)_(n)CN, halogen, C₁₋₆ alkyl, —(CH₂)_(n)—C(═O)OH,—(CH₂)_(n)—C(═O)OC₁₋₄ alkyl, —(CH₂)_(n)—OC₁₋₄ alkyl, —(CH₂)_(n)—C₃₋₁₀carbocycle, —(CH₂)_(n)-4- to 10-membered heterocycle, and —O-4- to10-membered heterocycle, wherein said carbocycle and heterocycle areoptionally substituted with R¹⁰;

R⁷ is independently selected from H, hydroxyl, alkoxy, halogen, amino,and C₁₋₃ alkyl;

R⁸ is independently selected from H, halogen, CN, NH₂, C₁₋₆ alkyl,haloalkyl, haloalkylcarbonylamine, alkylcarbonyl, alkoxy, haloalkoxy,—(CH₂)_(n)-aryl, —(CH₂)_(n)—C₃₋₆ cycloalkyl, and —(CH₂)_(n)-4- to6-membered heterocycle;

R⁹ is H or C₁₋₆ alkyl;

R¹⁰ is independently selected from H, C₁₋₆ alkyl (optionally substitutedwith R¹¹), C₂₋₆ alkenyl, C₂₋₆ alkynyl, —(CH₂)_(n)—C₃₋₆ cycloalkyl(optionally substituted with R¹¹), —O-4- to 10-membered heterocycle(optionally substituted with R¹¹), F, Cl, Br, CN, NO₂, ═O, CO₂H,—(CH₂)_(n)—OC₁₋₅ alkyl, —(CH₂)_(n)—OR¹¹, and —(CH₂)_(n)—NR¹¹R¹¹;

R¹¹, at each occurrence, is independently selected from H, C₁₋₅ alkyl,—(CH₂)_(n)—OH, C₃₋₆ cycloalkyl, and phenyl, or R¹¹ and R¹¹ together withthe nitrogen atom to which they are both attached form a heterocyclicring optionally substituted with C₁₋₄alkyl;

R¹² is C₁₋₆ alkyl optionally substituted with R¹¹;

n, at each occurrence, is an integer independently selected from 0, 1,2, 3, and 4; and

p, at each occurrence, is an integer independently selected from 0, 1,and 2.

In another aspect, the present invention provides compounds of Formula(II):

or stereoisomers, tautomers, pharmaceutically acceptable salts,solvates, or prodrugs thereof, wherein:

ring A is independently selected from a 6-membered aryl and a 5- to6-membered heterocycle, wherein said aryl and heterocycle aresubstituted with 1-4 R⁴;

ring B is a 5- to 10-membered heterocycle substituted with 1-4 R³;

G¹ is independently selected from a C₃₋₁₀ carbocycle and a 5- to10-membered heterocycle, wherein said carbocycle and heterocycle aresubstituted with 1-4 R⁸;

Y is independently selected from —NH—C(O)— and —C(O)—NH—;

R¹ and R² are independently selected from H, halogen, haloalkyl, C₁₋₄alkyl (optionally substituted with R⁶), hydroxyl, and alkoxy (optionallysubstituted with R⁶), and C₃₋₅ cycloalkyl optionally substituted withR⁶;

R³ is independently selected from H, ═O, halogen, haloalkyl, C₁₋₄alkyl(optionally substituted with R⁶), C₂₋₄ alkenyl (optionally substitutedwith R⁶), C₂₋₄ alkynyl (optionally substituted with R⁶), CN, NO₂,—(CH₂)_(n)—OR⁵, —(CH₂)_(n)—NR⁵R⁵, —(CH₂)_(n)—C(O)OR⁵,—(CH₂)_(n)—NR⁹C(O)OR⁵, —(CH₂)_(n)—NR⁹C(O)R⁵, —(CH₂)_(n)—NR⁹C(N—CN)NHR⁵,—(CH₂)_(n)—NR⁹C(NH)NHR⁵, —(CH₂)_(n)—N═CR⁹NR⁵R⁵, —(CH₂)_(n)—NR⁹C(O)NR⁵R⁵,—(CH₂)_(n)—C(O)NR⁵R⁵, —(CH₂)_(n)—NR⁹C(S)NR⁹C(O)R⁵,—(CH₂)_(n)—S(O)_(p)R¹², —(CH₂)_(n)—S(O)_(p)NR⁵R⁵,—(CH₂)_(n)—NR⁹S(O)_(p)NR⁵R⁵, —(CH₂)_(n)—NR⁹S(O)_(p)R¹², —(CH₂)_(n)—C₃₋₁₀carbocycle and —(CH₂)_(n)-4- to 10-membered heterocycle, wherein saidcarbocycle and heterocycle are optionally substituted with R⁶;optionally, two adjacent R³ groups on the carbocycle and heterocycle mayform a ring optionally substituted with R⁶;

R⁴ is independently selected from H, OH, halogen, CN, C₁₋₄ alkyl, C₁₋₄haloalkyl, C₁₋₄ alkoxy, —C(O)NH₂, —C(O)NH(C₁₋₄ alkyl), —C(O)N(C₁₋₄alkyl)₂, C₃₋₆ cycloalkyl, aryl, and 5- to 6-membered heterocycle,wherein said cycloalkyl, aryl and heterocycle are optionally substitutedwith R⁶;

R⁵ is independently selected from H, C₁₋₄ alkyl (optionally substitutedwith halogen, hydroxyl, alkoxy, carboxy, alkoxycarbonyl, amino,substituted amino), C₃₋₁₀ carbocycle and 4- to 10-membered heterocycle,wherein said carbocycle and heterocycle are optionally substituted withR⁶; alternatively, R⁵ and R⁵ together with the nitrogen atom to whichthey are both attached form a heterocyclic ring optionally substitutedwith R⁶;

R⁶ is independently selected from OH, ═O, —(CH₂)_(n)NH₂, —(CH₂)_(n)CN,halogen, C₁₋₆ alkyl, —(CH₂)_(n)—C(═O)OH, —(CH₂)_(n)—C(═O)OC₁₋₄ alkyl,—(CH₂)_(n)—OC₁₋₄ alkyl, —(CH₂)_(n)—C₃₋₁₀ carbocycle, —(CH₂)_(n)-4- to10-membered heterocycle, and —(CH₂)_(n)-4- to 10-membered heterocycle,wherein said carbocycle and heterocycle are optionally substituted withR¹⁰;

R⁷ is independently selected from H, hydroxyl, alkoxy, halogen, methyl,ethyl, and isopropyl;

R⁸ is independently selected from H, halogen, CN, NH₂, C₁₋₆ alkyl,haloalkyl, alkylcarbonyl, alkoxy, haloalkoxy, —(CH₂)_(n)-aryl,—(CH₂)_(n)—C₃₋₆ cycloalkyl, and —(CH₂)_(n)-4- to 6-membered heterocycle;

R⁹ is H or C₁₋₆ alkyl;

R¹⁰ is independently selected from C₁₋₆ alkyl (optionally substitutedwith R¹¹), C₂₋₆ alkenyl, C₂₋₆ alkynyl, —(CH₂)_(n)—C₃₋₆ cycloalkyl, —O-4-to 10-membered heterocycle (optionally substituted with R¹¹), F, Cl, Br,CN, NO₂, ═O, CO₂H, —(CH₂)_(n)—OC₁₋₅ alkyl, —(CH₂)_(n)—OR¹¹, and—(CH₂)_(n)—NR¹¹R¹¹;

R¹¹, at each occurrence, is independently selected from H, C₁₋₅ alkyl,—(CH₂)_(n)—OH, C₃₋₆ cycloalkyl, and phenyl, or R¹¹ and R¹¹ together withthe nitrogen atom to which they are both attached form a heterocyclicring optionally substituted with C₁₋₄alkyl;

R¹² is C₁₋₆ alkyl optionally substituted with R¹¹;

n, at each occurrence, is an integer independently selected from 0, 1,2, 3, and 4; and

p, at each occurrence, is an integer independently selected from 0, 1,and 2.

In another aspect, the present invention provides compounds of Formula(II), or stereoisomers, tautomers, pharmaceutically acceptable salts,solvates, or prodrugs thereof, wherein:

ring A is independently selected from

ring B is

is an optional bond;

G¹ is independently selected from

Y is —C(O)NH—;

R¹ and R² are independently selected from H and C₁₋₄ alkyl;

R³ is independently selected from H, F, C₁₋₄ alkyl, haloalkyl, and—NHC(O)OC₁₋₄ alkyl; provided only one R³ is present on the ring, and

R⁴ is independently selected from H, and C₁₋₄ alkyl; and

R⁷ is H.

In another aspect, the present invention provides compounds of Formula(IIa):

or stereoisomers, tautomers, pharmaceutically acceptable salts,solvates, or prodrugs thereof, wherein:

ring A is independently selected from 6-membered aryl and 5- to6-membered heterocyclyl;

ring B is 5- to 10-membered heterocyclyl or 5- to 10-memberedheterocyclyl comprising carbon atoms and 1-4 heteroatoms selected fromN, NR^(3c), O, and S(O)_(p);

G¹ is independently selected from C₃₋₆ carbocyclyl and 5- to 10-memberedheterocyclyl, wherein said carbocyclyl and heterocyclyl are substitutedwith 1-4 R⁸;

W is independently selected from (CR¹R²)₁₋₂, O, NH, and N(C₁₋₄ alkyl);

Y is independently selected from —CR¹³NH—, —NHC(═O)— and —C(═O)NH—;

R¹ and R² are independently selected from H, D, halogen, haloalkyl, C₁₋₄alkyl (optionally substituted with R⁶), hydroxyl, and alkoxy (optionallysubstituted with R⁶), and C₃₋₅ cycloalkyl optionally substituted withR⁶;

R³ is independently selected from H, halogen, C₁₋₄ alkyl (optionallysubstituted with R⁶), CN, —(CH₂)_(n)—OR⁵, —(CH₂)_(n)—NR⁵R⁵,—(CH₂)_(n)—C(═O)R⁵, and —(CH₂)_(n)—C(═O)OR⁵;

R^(3c) is independently selected from H, haloalkyl, C₁₋₄ alkyl(optionally substituted with R⁶), —(CH₂)₁₋₂—OH, C(═O)C₁₋₄ alkyl,—(CH₂)₁₋₂—C(═O)OH, —C(═O)OC₁₋₄ alkyl, S(═O)_(p)C₁₋₆ alkyl,—(CH₂)_(n)—C₃₋₁₀ carbocyclyl and —(CH₂)_(n)-4- to 10-memberedheterocyclyl, wherein said carbocyclyl and heterocyclyl are optionallysubstituted with R⁶;

R⁴ is independently selected from H, OH, halogen, CN, C₁₋₄ alkyl, C₁₋₄haloalkyl, C₁₋₄ alkoxy, —C(═O)NH₂, —C(═O)NH(C₁₋₄ alkyl), —C(═O)N(C₁₋₄alkyl)₂, C₃₋₆ cycloalkyl, aryl, and 5- to 6-membered heterocyclyl,wherein said cycloalkyl, aryl and heterocyclyl are optionallysubstituted with R⁶;

R⁵ is independently selected from H, C₁₋₄ alkyl (optionally substitutedwith halogen, hydroxyl, alkoxy, carboxy, alkoxycarbonyl, amino,substituted amino), C₃₋₁₀ carbocyclyl and 4- to 10-memberedheterocyclyl, wherein said carbocyclyl and heterocyclyl are optionallysubstituted with R⁶;

R⁶ is independently selected from H, OH, ═O, —(CH₂)_(n)NH₂,—(CH₂)_(n)CN, halogen, C₁₋₆ alkyl, —(CH₂)_(n)—C(═O)OH,—(CH₂)_(n)—C(═O)OC₁₋₄ alkyl, —(CH₂)_(n)—OC₁₋₄ alkyl,—(CH₂)_(n)—C(═O)NH₂, —(CH₂)_(n)—C₃₋₁₀ carbocyclyl, —(CH₂)_(n)-4- to10-membered heterocyclyl, and —(CH₂)_(n)-4- to 10-membered heterocyclyl,wherein said carbocyclyl and heterocyclyl are optionally substitutedwith R¹⁰;

R⁷ is independently selected from H, hydroxyl, halogen, C₁₋₂haloalkyl,and C₁₋₂alkyl;

R⁸ is independently selected from H, halogen, CN, NH₂, C₁₋₆ alkyl,haloalkyl, haloalkylcarbonylamino, arylamino, heteroarylamino,hydroxycarbonyl, haloalkylaminocarbonyl, arylalkylcarbonyl,alkylcarbonyl, alkoxy, haloalkoxy, —(CH₂)_(n)-aryl, —(CH₂)_(n)—C₃₋₆cycloalkyl, and —(CH₂)_(n)-4- to 12-membered heterocyclyl, wherein saidaryl, cycloalkyl, and heterocyclyl are optionally substituted with R¹⁰;

alternatively, two adjacent R⁸ groups and G₁ form a fused heterocyclicgroup selected from

R⁹ is H or C₁₋₆ alkyl;

R¹⁰ is independently selected from H, C₁₋₆ alkyl (optionally substitutedwith R¹¹), C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl (optionally substituted withR¹¹), —(CH₂)_(n)—C₃₋₆ cycloalkyl (optionally substituted with R¹¹),—(CH₂)_(n)—O-4- to 10-membered heterocyclyl (optionally substituted withR¹¹), F, Cl, Br, —(CH₂)_(n)CN, NO₂, ═O, C(═O)NR¹²R¹²,—(CH₂)_(n)C(═O)OR¹², Si(C₁₋₄ alkyl)₃, —(CH₂)_(n)—OR¹²,—(CH₂)_(n)—NR¹²R¹², and —S(═O)_(p)C₁₋₆ alkyl, NR¹²S(═O)_(p)C₁₋₆ alkyl,and S(═O)_(p)NR¹²R¹²;

R^(10′) is independently selected from H, C₁₋₆ alkyl (optionallysubstituted with R¹¹), aryl, —(CH₂)_(n)—C₃₋₆ cycloalkyl (optionallysubstituted with R¹¹), and —(CH₂)_(n)—O-4- to 10-membered heterocyclyl(optionally substituted with R¹¹);

R¹¹, at each occurrence, is independently selected from H, halogen, C₁₋₅alkyl, —(CH₂)_(n)—OH, C₃₋₆ cycloalkyl, and phenyl;

R¹², at each occurrence, is independently selected from H, C₁₋₅ alkyloptionally substituted with R¹¹, C₃₋₆ cycloalkyl, phenyl, andheterocyclyl, or R¹² and R¹² together with the nitrogen atom to whichthey are both attached form a heterocyclic ring optionally substitutedwith C₁₋₄alkyl;

R¹³ is, independently at each occurrence, selected from H, CF₃, C(═O)OH,C(═O)O(C₁₋₄ alkyl), and —C(═O)NH₂(C₁₋₄ alkoxy);

n, at each occurrence, is an integer independently selected from 0, 1,2, 3, and 4; and

p, at each occurrence, is an integer independently selected from 0, 1,and 2.

In another aspect, the present invention provides compounds of Formula(IIb):

or stereoisomers, tautomers, pharmaceutically acceptable salts,solvates, or prodrugs thereof, wherein:

ring A is independently selected from phenyl and 5- to 6-memberedheterocyclyl;

ring B is 5- to 10-membered heterocyclyl or 5- to 6-memberedheterocyclyl comprising carbon atoms and 1-4 heteroatoms selected fromN, NR^(3c), O, and S(O)_(p);

W is independently selected from (CR¹R²)₁₋₂, O, NH, and N(C₁₋₄ alkyl);

Y is independently selected from —CH₂NH—, —NHC(═O)— and —C(═O)NH—;

G³ is independently selected from N and CR^(8a);

G⁴ is independently selected from N and CR^(8e);

R¹ and R² are independently selected from H, D, halogen, CF₃, C₁₋₆alkyl, and hydroxyl;

R³ is independently selected from H, halogen, C₁₋₄alkyl (optionallysubstituted with R⁶), CN, —(CH₂)_(n)—OR⁵, —(CH₂)_(n)—NR⁵R⁵,—(CH₂)_(n)—C(═O)R⁵, and —(CH₂)_(n)—C(═O)OR⁵;

R^(3c) is independently selected from H, haloalkyl, C₁₋₄ alkyl(optionally substituted with R⁶), —(CH₂)₁₋₂—OH, C(═O)C₁₋₄ alkyl,—(CH₂)₁₋₂—C(═O)OH, —C(═O)OC₁₋₄ alkyl, S(═O)_(p)C₁₋₆ alkyl,—(CH₂)_(n)—C₃₋₁₀ carbocyclyl and —(CH₂)_(n)-4- to 10-memberedheterocyclyl, wherein said carbocyclyl and heterocyclyl are optionallysubstituted with R⁶;

R⁴ is independently selected from H, OH, F, Cl, Br, C₁₋₄ alkyl, C₁₋₄alkoxy, CF₃, CN, C(═O)NH₂, C₃₋₆ cycloalkyl, aryl, and 5- to 6-memberedheterocyclyl, wherein said cycloalkyl, aryl and heterocyclyl areoptionally substituted with R⁶;

R⁵ is independently selected from H, and C₁₋₄ alkyl optionallysubstituted with halogen and hydroxyl;

R⁶ is independently selected from H, —(CH₂)_(n)—OH, ═O, NH₂,—(CH₂)_(n)—CN, halogen, C₁₋₆ alkyl, —(CH₂)_(n)—C(═O)OH,—(CH₂)_(n)—C(═O)OC₁₋₄ alkyl, —(CH₂)_(n)—OC₁₋₄ alkyl, —(CH₂)_(n)—C₃₋₆cycloalkyl, —(CH₂)_(n)-4- to 10-membered heterocyclyl, and—O—(CH₂)_(n)-4- to 10-membered heterocyclyl, wherein said cycloalkyl andheterocyclyl are optionally substituted with R¹⁰;

R⁷ is independently selected from H, F, Cl, Br, CF₃, and CH₃;

R^(8a) is independently selected from H, F, Cl, Br, I, —(CH₂)_(n)CN,—(CH₂)_(n)NH₂, C₁₋₂alkyl, C₁₋₂haloalkyl, OH, OC₁₋₂alkyl, OC₁₋₂haloalkyl,C(═O)OH, C(═O)OC₁₋₃alkyl, C(═O)NH₂, C(═O)NHC₁₋₂haloalkyl,C(═O)NHarylalkyl, C(═O)C₁₋₃alkyl, NHC(═O)OC₁₋₂alkyl,NHC(═O)C₁₋₂haloalkyl, NH-aryl, NH-heteroaryl, aryl, C₃₋₆ cycloalkyl, and4- to 12-membered heterocyclyl, wherein said aryl, cycloalkyl andheterocyclyl is optionally substituted with R¹⁰;

R^(8b) is independently selected from H and F;

R^(8c) is independently selected from H, F, Cl, methyl, ethyl,isopropyl, OCHF₂, and OCH₃;

R^(8d) is independently selected from H, F, and Cl;

R^(8e) is independently selected from H, F, and Cl;

R¹⁰ is independently selected from H, C₁₋₆ alkyl (optionally substitutedwith R¹¹), C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl (optionally substituted withR¹¹), —(CH₂)_(n)—C₃₋₆ cycloalkyl (optionally substituted with R¹¹),—(CH₂)_(n)—O-4- to 10-membered heterocyclyl (optionally substituted withR¹¹), F, Cl, Br, CN, NO₂, ═O, CONR¹²R¹², —(CH₂)_(n)C(═O)OR¹², Si(C₁₋₄alkyl)₃, —(CH₂)_(n)—OR¹², and —(CH₂)_(n)—NR¹²R¹², —S(═O)_(p)C₁₋₆ alkyl,NR¹²S(═O)_(p)C₁₋₆ alkyl, and S(═O)_(p)NR¹²R¹²;

R¹¹, at each occurrence, is independently selected from H, halogen, C₁₋₅alkyl, —(CH₂)_(n)—OH, C₃₋₆ cycloalkyl, and phenyl;

R¹², at each occurrence, is independently selected from H, C₁₋₅ alkyloptionally substituted with R¹¹, C₃₋₆ cycloalkyl, phenyl, andheterocyclyl, or R¹² and R¹² together with the nitrogen atom to whichthey are both attached form a heterocyclic ring optionally substitutedwith C₁₋₄alkyl;

n, at each occurrence, is an integer independently selected from 0, 1,and 2; and

p, at each occurrence, is an integer independently selected from 0, 1,and 2.

In another aspect, the present invention provides compounds of Formula(IIb), or stereoisomers, tautomers, pharmaceutically acceptable salts,solvates, or prodrugs thereof, wherein:

ring A is independently selected from phenyl and 5- to 6-memberedheterocyclyl;

ring B is 5- to 6-membered heteroaryl comprising carbon atoms and 1-4heteroatoms selected from N and NR^(3c);

W is independently selected from (CR¹R²)₁₋₂, O, NH, and N(C₁₋₄ alkyl);

Y is independently selected from —CH₂NH—, —NHC(═O)— and —C(═O)NH—;

G³ is CR^(8a);

G⁴ is CR^(8e);

R¹ and R² are independently selected from H, D, halogen, CF₃, C₁₋₆alkyl, and hydroxyl;

R³ is independently selected from H, halogen, C₁₋₄alkyl (optionallysubstituted with R⁶), CN, —(CH₂)_(n)—OR⁵, —(CH₂)_(n)—C(═O)R⁵, and—(CH₂)_(n)—C(═O)OR⁵;

R^(3c) is independently selected from H, haloalkyl, C₁₋₄ alkyl(optionally substituted with R⁶), —(CH₂)₁₋₂—OH, C(═O)C₁₋₄ alkyl,—(CH₂)₁₋₂—C(═O)OH, —C(═O)OC₁₋₄ alkyl, S(═O)_(p)C₁₋₆ alkyl,—(CH₂)_(n)—C₃₋₁₀ carbocyclyl and —(CH₂)_(n)-4- to 10-memberedheterocyclyl, wherein said carbocyclyl and heterocyclyl are optionallysubstituted with R⁶;

R⁴ is independently selected from H, OH, F, Cl, Br, C₁₋₄ alkyl, C₁₋₄alkoxy, CF₃, CN, C(═O)NH₂, C₃₋₆ cycloalkyl, aryl, and 5- to 6-memberedheterocyclyl, wherein said cycloalkyl, aryl and heterocyclyl areoptionally substituted with R⁶;

R⁵ is independently selected from H and C₁₋₄ alkyl;

R⁶ is independently selected from H, —(CH₂)_(n)—OH, ═O, NH₂,—(CH₂)_(n)—CN, halogen, C₁₋₆ alkyl, —(CH₂)_(n)—C(═O)OH,—(CH₂)_(n)—C(═O)OC₁₋₄ alkyl, —(CH₂)_(n)—OC₁₋₄ alkyl, —(CH₂)_(n)—C₃₋₆cycloalkyl, —(CH₂)_(n)-4- to 10-membered heterocyclyl, and—O—(CH₂)_(n)-4- to 10-membered heterocyclyl, wherein said cycloalkyl andheterocyclyl are optionally substituted with R¹⁰;

R⁷ is independently selected from H, F, Cl, Br, and methyl;

R^(8a) is independently selected from H, F, Cl, Br, I, —(CH₂)_(n)CN,—(CH₂)_(n)NH₂, CH₃CHF₂, CCH₃F₂, CF₃, OH, OCH₃, OCF₃, OCHF₂, C(═O)CH₃,C(═O)OH, C(═O)OCH₃, C(═O)NH₂, C(═O)NHCH₂CF₃, C(═O)NHCH₂Ph, NHC(═O)OCH₃,NHC(═O)CF₃,

R^(8b) is independently selected from H and F;

R^(8c) is independently selected from H, F, Cl, methyl, ethyl,isopropyl, and OCH₃;

R^(8d) is independently selected from H, F, and Cl;

R^(8e) is independently selected from H, F, and Cl;

R¹⁰ is independently selected from H, C₁₋₆ alkyl (optionally substitutedwith R¹¹), C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl (optionally substituted withR¹¹), —(CH₂)_(n)—C₃₋₆ cycloalkyl (optionally substituted with R¹¹),—(CH₂)_(n)—O-4- to 10-membered heterocyclyl (optionally substituted withR¹¹), F, Cl, Br, CN, NO₂, ═O, CONR¹²R¹², —(CH₂)_(n)—C(═O)OR¹², Si(C₁₋₄alkyl)₃, —(CH₂)_(n)—OR¹², —(CH₂)_(n)—NR¹²R¹², —S(═O)_(p)C₁₋₆ alkyl,NR¹²S(═O)_(p)C₁₋₆ alkyl, and S(═O)_(p)NR¹²R¹²;

R^(10′) is independently selected from H, C₁₋₆ alkyl (optionallysubstituted with R¹¹), aryl, —(CH₂)_(n)—C₃₋₆ cycloalkyl (optionallysubstituted with R¹¹), and —(CH₂)_(n)—O-4- to 10-membered heterocyclyl(optionally substituted with R¹¹);

R¹¹, at each occurrence, is independently selected from H, halogen, C₁₋₅alkyl, —(CH₂)_(n)—OH, C₃₋₆ cycloalkyl, and phenyl;

R¹², at each occurrence, is independently selected from H, C₁₋₅ alkyloptionally substituted with R¹¹, C₃₋₆ cycloalkyl, phenyl, andheterocyclyl, or R¹² and R¹² together with the nitrogen atom to whichthey are both attached form a heterocyclic ring optionally substitutedwith C₁₋₄alkyl;

n, at each occurrence, is an integer independently selected from 0, 1,and 2; and

p, at each occurrence, is an integer independently selected from 0, 1,and 2.

In another aspect, the present invention provides compounds of Formula(IIc):

or stereoisomers, tautomers, pharmaceutically acceptable salts,solvates, or prodrugs thereof, wherein:

ring A is independently selected from phenyl and 5- to 6-memberedheterocyclyl;

ring B is 5- to 6-membered heteroaryl comprising carbon atoms and 1-3heteroatoms selected from N and NR^(3c);

W is independently selected from (CR¹R²)₁₋₂, O, NH, and N(C₁₋₄ alkyl);

Y is independently selected from —CH₂NH—, —NHC(═O)— and —C(═O)NH—;

R¹ and R² are independently selected from H, D, F, C₁₋₄ alkyl, andhydroxyl;

R³ is independently selected from H, halogen, haloalkyl, C₁₋₄alkyl(optionally substituted with R⁶), and CN;

R^(3c) is independently selected from H, haloalkyl, C₁₋₄ alkyl(optionally substituted with R⁶), —(CH₂)₁₋₂—OH, C(═O)C₁₋₄ alkyl,—(CH₂)₁₋₂—C(═O)OH, —C(═O)OC₁₋₄ alkyl, S(═O)_(p)C₁₋₆ alkyl,—(CH₂)_(n)—C₃₋₁₀ carbocyclyl and —(CH₂)_(n)-4- to 10-memberedheterocyclyl, wherein said carbocyclyl and heterocyclyl are optionallysubstituted with R⁶;

R⁴ is independently selected from H, OH, F, Cl, Br, C₁₋₄ alkyl, C₁₋₄alkoxy, CF₃, CN; C(═O)NH₂, C₃₋₆ cycloalkyl, aryl, and 5- to 6-memberedheterocyclyl;

R⁶ is independently selected from H, —(CH₂)_(n)—OH, ═O, NH₂,—(CH₂)_(n)—CN, halogen, C₁₋₆ alkyl, —(CH₂)_(n)—C(═O)OH,—(CH₂)_(n)—C(═O)OC₁₋₄ alkyl, —(CH₂)_(n)—OC₁₋₄ alkyl, —(CH₂)_(n)—C₃₋₆cycloalkyl, —(CH₂)_(n)-4- to 10-membered heterocyclyl, and—O—(CH₂)_(n)-4- to 10-membered heterocyclyl, wherein said cycloalkyl andheterocyclyl are optionally substituted with R¹⁰;

R^(8b) is independently selected from H and F;

R^(8c) is independently selected from H, F, Cl, CH₃, and OCH₃;

R¹⁰ is independently selected from H, C₁₋₆ alkyl (optionally substitutedwith R¹¹), C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, —(CH₂)_(n)—C₃₋₆ cycloalkyl(optionally substituted with R¹¹), —(CH₂)_(n)—O-4- to 10-memberedheterocyclyl (optionally substituted with R¹¹), F, Cl, Br, CN, NO₂, ═O,C(═O)NR¹²R¹², C(═O)OR¹², Si(C₁₋₄ alkyl)₃, —(CH₂)_(n)—OR¹²,—(CH₂)_(n)—NR¹²R¹², —S(═O)_(p)C₁₋₆ alkyl, NR¹²S(═O)_(p)C₁₋₆ alkyl, andS(═O)_(p)NR¹²R¹²;

R¹¹, at each occurrence, is independently selected from H, halogen, C₁₋₅alkyl, —(CH₂)_(n)—OH, C₃₋₆ cycloalkyl, and phenyl;

R¹², at each occurrence, is independently selected from H, C₁₋₅ alkyl,C₃₋₆ cycloalkyl, phenyl, and heterocyclyl, or R¹² and R¹² together withthe nitrogen atom to which they are both attached form a heterocyclicring optionally substituted with C₁₋₄alkyl;

n, at each occurrence, is an integer independently selected from 0, 1,and 2; and

p, at each occurrence, is an integer independently selected from 0, 1,and 2.

In another aspect, the present invention provides compounds of Formula(IId):

or stereoisomers, tautomers, pharmaceutically acceptable salts,solvates, or prodrugs thereof, wherein:

is an optional bond;

ring A is independently selected from phenyl and 5- to 6-memberedheterocyclyl;

W is independently selected from CHR^(1a), O, NH, and N(C₁₋₄ alkyl);

G⁵ is independently selected from CH₂ and NR^(3c);

G⁶ is independently selected from CH₂ and NR^(3c);

provided when G⁵ is CH₂, G⁶ is NR^(3c); when G⁵ is NR^(3c), G⁶ is CH₂and only one R^(3c) is present on the ring;

Y is independently selected from —NHC(═O)— and —C(═O)NH—;

R¹ is independently selected from H and C₁₋₄ alkyl;

R^(1a) is independently selected from H, D, F, CH₃, and OH;

R² is independently selected from H, D, and OH;

R^(3c) is independently selected from H, haloalkyl, C₁₋₄alkyl(optionally substituted with R⁶), —(CH₂)₁₋₂—OH, C(═O)C₁₋₄ alkyl,—(CH₂)₁₋₂—C(═O)OH, —C(═O)OC₁₋₄ alkyl, S(═O)_(p)C₁₋₆ alkyl, phenyloptionally substituted with R⁶, 5- to 6-membered heterocyclyl optionallysubstituted with R⁶, and 5- to 6-membered heteroaryl optionallysubstituted with R⁶;

R⁴ is independently selected from H, OH, F, Cl, Br, C₁₋₄ alkyl, C₁₋₄alkoxy, CF₃, CN, and C(═O)NH₂;

R⁶ is independently selected from H, —(CH₂)_(n)—OH, ═O, NH₂,—(CH₂)_(n)—CN, halogen, C₁₋₆ alkyl, —(CH₂)_(n)—C(═O)OH,—(CH₂)_(n)—C(═O)OC₁₋₄ alkyl, —(CH₂)_(n)—OC₁₋₄ alkyl, —(CH₂)_(n)—C₃₋₆cycloalkyl, —(CH₂)_(n)-4- to 10-membered heterocyclyl, and—O—(CH₂)_(n)-4- to 10-membered heterocyclyl, wherein said cycloalkyl andheterocyclyl are optionally substituted with R¹⁰;

R^(8b) is independently selected from H and F;

R^(8c) is independently selected from H, F, Cl, CH₃, and OCH₃;

R¹⁰ is independently selected from H, C₁₋₆ alkyl (optionally substitutedwith R¹¹), aryl, —(CH₂)_(n)—C₃₋₆ cycloalkyl (optionally substituted withR¹¹), —(CH₂)_(n)—O-4- to 10-membered heterocyclyl (optionallysubstituted with R¹¹), F, Cl, Br, CN, NO₂, ═O, C(═O)NR¹²R¹², C(═O)OR¹²,Si(C₁₋₄ alkyl)₃, —(CH₂)_(n)—OR¹², and —(CH₂)_(n)—NR¹²R¹², —S(═O)_(p)C₁₋₆alkyl, NR¹²S(═O)_(p)C₁₋₆ alkyl, and S(═O)_(p)NR¹²R¹²;

R¹¹, at each occurrence, is independently selected from H, halogen, C₁₋₅alkyl, —(CH₂)_(n)—OH, C₃₋₆ cycloalkyl, and phenyl;

R¹², at each occurrence, is independently selected from H, C₁₋₅ alkyl,C₃₋₆ cycloalkyl, phenyl, and heterocyclyl, or R¹² and R¹² together withthe nitrogen atom to which they are both attached form a heterocyclicring optionally substituted with C₁₋₄alkyl;

n, at each occurrence, is an integer independently selected from 0, 1,and 2; and

p, at each occurrence, is an integer independently selected from 0, 1,and 2.

In another aspect, the present invention provides compounds of Formula(IIe):

or stereoisomers, tautomers, pharmaceutically acceptable salts,solvates, or prodrugs thereof, wherein:

ring A is independently selected from

R¹ is independently selected from H and C₁₋₄ alkyl;

R^(1a) is independently selected from H, D, F, CH₃, and OH;

R² is independently selected from H, D, and OH;

R^(3c) is independently selected from H, CHF₂, CD₃, CH₃, CH₂CH₂OH,CH₂C(═O)OH, SO₂CH₃, phenyl optionally substituted with R⁶, and 5- to6-membered heteroaryl optionally substituted with R⁶;

R⁴ is independently selected from H, F, and C(═O)NH₂;

R⁶ is independently selected from H, —(CH₂)_(n)—OH, ═O, NH₂,—(CH₂)_(n)—CN, halogen, C₁₋₆ alkyl, —(CH₂)_(n)—C(═O)OH,—(CH₂)_(n)—C(═O)OC₁₋₄ alkyl, —(CH₂)_(n)—OC₁₋₄ alkyl, —(CH₂)_(n)—C₃₋₆cycloalkyl, —(CH₂)_(n)-4- to 10-membered heterocyclyl, and—O—(CH₂)_(n)-4- to 10-membered heterocyclyl, wherein said cycloalkyl andheterocyclyl are optionally substituted with R¹⁰;

R^(8b) is independently selected from H and F;

R^(8c) is independently selected from H, F, Cl, CH₃, and OCH₃;

R¹⁰ is independently selected from H, CF₃, CHF₂, CH₂F, aryl,—(CH₂)_(n)—C₃₋₆ cycloalkyl (optionally substituted with R¹¹), heteroaryl(optionally substituted with R¹¹), —(CH₂)_(n)—O-4- to 10-memberedheterocyclyl (optionally substituted with R¹¹), F, Cl, Br, CN, NO₂, ═O,C(═O)NR¹²R¹², —(CH₂)_(n)—C(═O)OR¹², Si(C₁₋₄ alkyl)₃, —(CH₂)_(n)—OR¹²,—(CH₂)_(n)—NR¹²R¹², —S(═O)_(p)C₁₋₆ alkyl, NR¹²S(═O)_(p)C₁₋₆ alkyl, andS(═O)_(p)NR¹²R¹²;

R¹¹, at each occurrence, is independently selected from H, halogen, C₁₋₅alkyl, —(CH₂)_(n)—OH, C₃₋₆ cycloalkyl, and phenyl;

R¹², at each occurrence, is independently selected from H, C₁₋₅ alkyl,C₃₋₆ cycloalkyl, phenyl, and heterocyclyl, or R¹² and R¹² together withthe nitrogen atom to which they are both attached form a heterocyclicring optionally substituted with C₁₋₄alkyl; and

n, at each occurrence, is an integer independently selected from 0, 1,and 2.

In another aspect, the present invention provides compounds of Formula(IIf):

or stereoisomers, tautomers, pharmaceutically acceptable salts,solvates, or prodrugs thereof, wherein:

ring A is independently selected from

R¹ is independently selected from H and C₁₋₄ alkyl;

R^(1a) is independently selected from H, D, F, CH₃, and OH;

R² is independently selected from H, D, and OH;

R^(3c) is independently selected from H, CHF₂, CD₃, CH₃, SO₂CH₃, phenyloptionally substituted with R⁶, and 5- to 6-membered heterocyclyloptionally substituted with R⁶, 5- to 6-membered heteroaryl optionallysubstituted with R⁶;

R⁴ is independently selected from H and F;

R⁶ is independently selected from OH, ═O, NH₂, CN, halogen, C₁₋₆ alkyl,—(CH₂)_(n)—C₃₋₆ cycloalkyl, —(CH₂)_(n)-4- to 10-membered heterocyclyl,and —O—(CH₂)_(n)-4- to 10-membered heterocyclyl, wherein said cycloalkyland heterocyclyl are optionally substituted with R¹⁰;

R^(8b) is independently selected from H and F;

R^(8c) is independently selected from H, F, Cl, CH₃, and OCH₃;

R¹⁰ is independently selected from H, CF₃, CHF₂, C(CH₃)₂OH, aryl,—(CH₂)_(n)—C₃₋₆ cycloalkyl (optionally substituted with R¹¹),—(CH₂)_(n)—O-4- to 10-membered heterocyclyl (optionally substituted withR¹¹), F, Cl, Br, CN, NO₂, ═O, C(═O)NR¹²R¹², C(═O)OR¹², Si(C₁₋₄ alkyl)₃,—(CH₂)_(n)—OR¹², —(CH₂)_(n)—NR¹²R¹², —S(═O)_(p)C₁₋₆ alkyl,NR¹²S(═O)_(p)C₁₋₆ alkyl, and S(═O)_(p)NR¹²R¹²;

R¹¹, at each occurrence, is independently selected from H, halogen, C₁₋₅alkyl, —(CH₂)_(n)—OH, C₃₋₆ cycloalkyl, and phenyl;

R¹², at each occurrence, is independently selected from H, C₁₋₅ alkyl,C₃₋₆ cycloalkyl, phenyl, and heterocyclyl, or R¹² and R¹² together withthe nitrogen atom to which they are both attached form a heterocyclicring optionally substituted with C₁₋₄alkyl; and

n, at each occurrence, is an integer independently selected from 0, 1,and 2.

In another aspect, the present invention provides compounds of Formula(IIf): or stereoisomers, tautomers, pharmaceutically acceptable salts,solvates, or prodrugs thereof, wherein:

ring A is independently selected from

R¹ is independently selected from H and C₁₋₄ alkyl;

R^(1a) is independently selected from H, D, F, CH₃, and OH;

R² is independently selected from H, D, and OH;

R^(3c) is independently selected from H, CHF₂, CD₃, CH₃, SO₂CH₃, phenyloptionally substituted with R⁶, and heterocyclyl selected from

R⁴ is independently selected from H and F;

R⁶ is independently selected from H, OH, OC₁₋₄ alkyl, CN, F, Cl, andC₁₋₄ alkyl;

R^(8b) is independently selected from H and F;

R^(8c) is independently selected from H, F, Cl, CH₃, and OCH₃;

R¹⁰ is independently selected from H, CF₃, CHF₂, C(CH₃)₂OH, aryl,—(CH₂)_(n)—C₃₋₆ cycloalkyl (optionally substituted with R¹¹),—(CH₂)_(n)—O-4- to 10-membered heterocyclyl (optionally substituted withR¹¹), F, Cl, Br, CN, NO₂, ═O, C(═O)NR¹²R¹², C(═O)OR¹², Si(C₁₋₄ alkyl)₃,—(CH₂)_(n)—OR¹², —(CH₂)_(n)—NR¹²R¹², —S(═O)_(p)C₁₋₆ alkyl,NR¹²S(═O)_(p)C₁₋₆ alkyl, and S(═O)_(p)NR¹²R¹²;

R¹¹, at each occurrence, is independently selected from H, halogen, C₁₋₅alkyl, —(CH₂)_(n)—OH, C₃₋₆ cycloalkyl, and phenyl;

R¹², at each occurrence, is independently selected from H, C₁₋₅ alkyl,C₃₋₆ cycloalkyl, phenyl, and heterocyclyl, or R¹² and R¹² together withthe nitrogen atom to which they are both attached form a heterocyclicring optionally substituted with C₁₋₄alkyl; and

n, at each occurrence, is an integer independently selected from 0, 1,and 2.

In another aspect, the present invention provides compounds of Formula(IIg):

or stereoisomers, tautomers, pharmaceutically acceptable salts,solvates, or prodrugs thereof, wherein:

ring A is independently selected from

R¹ is independently selected from H and C₁₋₄ alkyl;

R^(1a) is independently selected from H, F, CH₃, and OH;

R² is independently selected from H and OH;

R^(3c) is independently selected from H, CHF₂, CD₃, and CH₃;

R⁴ is independently selected from H and F;

R^(8b) is independently selected from H and F;

R^(8c) is independently selected from H, F, Cl, CH₃, and OCH₃;

R¹⁰ is independently selected from H, CF₃, CHF₂, aryl, —(CH₂)_(n)—C₃₋₆cycloalkyl (optionally substituted with R¹¹), —(CH₂)_(n)—O-4- to10-membered heterocyclyl (optionally substituted with R¹¹), F, Cl, Br,CN, NO₂, ═O, C(═O)NR¹²R¹², C(═O)OR¹², Si(C₁₋₄ alkyl)₃, —(CH₂)_(n)—OR¹²,—(CH₂)_(n)—NR¹²R¹², —S(═O)_(p)C₁₋₆ alkyl, NR¹²S(═O)_(p)C₁₋₆ alkyl, andS(═O)_(p)NR¹²R¹²;

R¹¹, at each occurrence, is independently selected from H, halogen, C₁₋₅alkyl, —(CH₂)_(n)—OH, C₃₋₆ cycloalkyl, and phenyl;

R¹², at each occurrence, is independently selected from H, C₁₋₅ alkyl,C₃₋₆ cycloalkyl, phenyl, and heterocyclyl, or R¹² and R¹² together withthe nitrogen atom to which they are both attached form a heterocyclicring optionally substituted with C₁₋₄alkyl; and

n, at each occurrence, is an integer independently selected from 0, 1,and 2.

In another aspect, the present invention provides compounds of Formula(IIIa):

or stereoisomers, tautomers, pharmaceutically acceptable salts,solvates, or prodrugs thereof, wherein:

ring A is independently selected from phenyl and a 5- to 6-memberedheterocycle;

G¹ is independently selected from aryl, C₃₋₆cycloalkyl and a 5- to6-membered heterocycle, wherein said aryl, cycloalkyl and heterocycleare substituted with 1-4 R⁸; G² is N;

R¹ and R² are independently selected from H, halogen, CF₃, C₁₋₆ alkyl,and hydroxyl;

R³ is independently selected from H, halogen, haloalkyl, C₁₋₄alkyl(optionally substituted with R⁶), C₂₋₄alkenyl (optionally substitutedwith R⁶), CN, NO₂, —(CH₂)_(n)—OR⁵, —(CH₂)_(n)—NR⁵R⁵,—(CH₂)_(n)—C(═O)OR⁵, —(CH₂)_(n)—NHC(═O)OR⁵, —(CH₂)_(n)—NHC(═O)R⁵,—(CH₂)_(n)—NHC(N—CN)NHR⁵, —(CH₂)_(n)—NHC(NH)NHR⁵, —(CH₂)_(n)—N═CHNR⁵R⁵,—(CH₂)_(n)—NHC(═O)NR⁵R⁵, —(CH₂)_(n)—C(═O)NR⁵R⁵,—(CH₂)_(n)—NHC(S)NR⁹C(═O)R⁵, —(CH₂)_(n)—S(═O)_(p)C₁₋₆ alkyl optionallysubstituted with R¹¹, —(CH₂)_(n)—S(═O)_(p)NR⁵R⁵,—(CH₂)_(n)—NHS(═O)_(p)NR⁵R⁵, —(CH₂)_(n)—NHS(═O)_(p)C₁₋₆ alkyl optionallysubstituted with R¹¹, —(CH₂)_(n)—C₃₋₁₀ carbocycle and —(CH₂)_(n)-4- to10-membered heterocycle, wherein said carbocycle and heterocycle areoptionally substituted with R⁶; optionally, two adjacent R³ groups onthe carbocycle and heterocycle may form a ring optionally substitutedwith R⁶;

R^(3a) is independently selected from H and halogen;

R^(3b) is independently selected from H, halogen, methyl, and CN;

R⁴ is independently selected from H, OH, F, Cl, Br, C₁₋₄ alkyl, C₁₋₄alkoxy, CF₃, CN, C₃₋₆ cycloalkyl, aryl, and 5- to 6-memberedheterocycle, wherein said cycloalkyl, aryl and heterocycle areoptionally substituted with R⁶;

R⁵ is independently selected from H, C₁₋₄ alkyl (optionally substitutedwith halogen, hydroxyl, alkoxy, carboxy, alkoxycarbonyl, amino,substituted amino), —(CH₂)_(n)—C₃₋₁₀ carbocycle and —(CH₂)_(n)-4- to10-membered heterocycle, wherein said carbocycle and heterocycle areoptionally substituted with R⁶;

R⁶ is independently selected from —(CH₂)_(n)—OH, ═O, NH₂, —(CH₂)_(n)—CN,halogen, C₁₋₆ alkyl, —(CH₂)_(n)—C(═O)OH, —(CH₂)_(n)—C(═O)OC₁₋₄ alkyl,—(CH₂)_(n)—OC₁₋₄ alkyl, —(CH₂)_(n)—C₃₋₆ cycloalkyl, —(CH₂)_(n)-4- to10-membered heterocycle, and —O—(CH₂)_(n)-4- to 10-membered heterocycle,wherein said cycloalkyl and heterocycle are optionally substituted withR¹⁰;

R⁷ is independently selected from H, F, Cl, and methyl;

R⁸ is independently selected from H, halogen, CN, NH₂, C₁₋₆ alkyl,haloalkyl, alkylcarbonyl, alkoxy, haloalkoxy, aryl, C₃₋₆ cycloalkyl, and4- to 6-membered heterocycle, wherein said aryl, cycloalkyl, andheterocycle are optionally substituted with R¹⁰;

R¹⁰ is independently selected from H, C₁₋₆ alkyl (optionally substitutedwith R¹¹), C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, —(CH₂)_(n)—C₃₋₆ cycloalkyl(optionally substituted with R¹¹), —(CH₂)_(n)—O-4- to 10-memberedheterocycle (optionally substituted with R¹¹), F, Cl, Br, CN, NO₂, ═O,C(═O)NR¹²R¹², C(═O)OR¹², Si(C₁₋₄ alkyl)₃, —(CH₂)_(n)—OR¹², and—(CH₂)_(n)—NR¹²R¹²;

R¹¹, at each occurrence, is independently selected from H, halogen, C₁₋₅alkyl, —(CH₂)_(n)—OH, C₃₋₆ cycloalkyl, and phenyl;

R¹², at each occurrence, is independently selected from H, C₁₋₅ alkyl,C₃₋₆ cycloalkyl, phenyl, and heterocycle, or R¹² and R¹² together withthe nitrogen atom to which they are both attached form a heterocyclicring optionally substituted with C₁₋₄alkyl;

n, at each occurrence, is an integer independently selected from 0, 1,and 2; and

p, at each occurrence, is an integer independently selected from 0, 1,and 2.

In another aspect, the present invention provides compounds of Formula(IIIb):

or stereoisomers, tautomers, pharmaceutically acceptable salts,solvates, or prodrugs thereof, wherein:

ring A is independently selected from phenyl and 5- to 6-memberedheterocyclyl;

G¹ is independently selected from aryl, C₃₋₆cycloalkyl and 5- to6-membered heterocyclyl, wherein said aryl, cycloalkyl and heterocyclylare substituted with 1-4 R⁸;

G² is independently selected from N and CR^(3b);

G⁷ is independently selected from N and CR³;

G⁸ is independently selected from N and CR³;

provided at least one of G², G⁶, and G⁷ is N;

R¹ and R² are independently selected from H, halogen, CF₃, C₁₋₆ alkyl,and hydroxyl;

R³ is independently selected from H, halogen, haloalkyl, C₁₋₄alkyl(optionally substituted with R⁶), C₂₋₄alkenyl (optionally substitutedwith R⁶), CN, NO₂, —(CH₂)_(n)—OR⁵, —(CH₂)_(n)—NR⁵R⁵,—(CH₂)_(n)—C(═O)OR⁵, —(CH₂)_(n)—NHC(═O)OR⁵, —(CH₂)_(n)—NHC(═O)R⁵,—(CH₂)_(n)—NHC(N—CN)NHR⁵, —(CH₂)_(n)—NHC(NH)NHR⁵, —(CH₂)_(n)—N═CHNR⁵R⁵,—(CH₂)_(n)—NHC(═O)NR⁵R⁵, —(CH₂)_(n)—C(═O)NR⁵R⁵,—(CH₂)_(n)—NHC(S)NR⁹C(═O)R⁵, —(CH₂)_(n)—S(═O)_(p)C₁₋₆ alkyl optionallysubstituted with R¹¹, —(CH₂)_(n)—S(═O)_(p)NR⁵R⁵,—(CH₂)_(n)—NHS(═O)_(p)NR⁵R⁵, —(CH₂)_(n)—NHS(═O)_(p)C₁₋₆ alkyl optionallysubstituted with R¹¹, —(CH₂)_(n)—C₃₋₁₀ carbocyclyl and —(CH₂)_(n)-4- to10-membered heterocyclyl, wherein said carbocyclyl and heterocyclyl areoptionally substituted with R⁶; optionally, two adjacent R³ groups onthe carbocyclyl and heterocyclyl may form a ring optionally substitutedwith R⁶;

R^(3a) is independently selected from H and halogen;

R^(3b) is independently selected from H, halogen, methyl, and CN;

R⁴ is independently selected from H, OH, F, Cl, Br, C₁₋₄ alkyl, C₁₋₄alkoxy, CF₃, CN, C₃₋₆ cycloalkyl, aryl, and 5- to 6-memberedheterocyclyl, wherein said cycloalkyl, aryl and heterocyclyl areoptionally substituted with R⁶;

R⁵ is independently selected from H, C₁₋₄ alkyl (optionally substitutedwith halogen, hydroxyl, alkoxy, carboxy, alkoxycarbonyl, amino,substituted amino), —(CH₂)_(n)—C₃₋₁₀ carbocyclyl and —(CH₂)_(n)-4- to10-membered heterocyclyl, wherein said carbocyclyl and heterocyclyl areoptionally substituted with R⁶;

R⁶ is independently selected from —(CH₂)_(n)—OH, ═O, NH₂, —(CH₂)_(n)—CN,halogen, C₁₋₆ alkyl, —(CH₂)_(n)—C(═O)OH, —(CH₂)_(n)—C(═O)OC₁₋₄ alkyl,—(CH₂)_(n)—OC₁₋₄ alkyl, —(CH₂)_(n)—C₃₋₆ cycloalkyl, —(CH₂)_(n)-4- to10-membered heterocyclyl, and —O—(CH₂)_(n)-4- to 10-memberedheterocyclyl, wherein said cycloalkyl and heterocyclyl are optionallysubstituted with R¹⁰;

R⁷ is independently selected from H, F, Cl, and methyl;

R⁸ is independently selected from H, halogen, CN, NH₂, C₁₋₆ alkyl,haloalkyl, alkylcarbonyl, alkoxy, haloalkoxy, aryl, C₃₋₆ cycloalkyl, and4- to 12-membered heterocyclyl, wherein said aryl, cycloalkyl, andheterocyclyl are optionally substituted with R¹⁰;

R¹⁰ is independently selected from H, C₁₋₆ alkyl (optionally substitutedwith R¹¹), C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, —(CH₂)_(n)—C₃₋₆ cycloalkyl(optionally substituted with R¹¹), —(CH₂)_(n)—O-4- to 10-memberedheterocyclyl (optionally substituted with R¹¹), F, Cl, Br, CN, NO₂, ═O,C(═O)NR¹²R¹², C(═O)OR¹², Si(C₁₋₄ alkyl)₃, —(CH₂)_(n)—OR¹²,—(CH₂)_(n)—NR¹²R¹², —S(═O)_(p)C₁₋₆ alkyl, NR¹²S(═O)_(p)C₁₋₆ alkyl, andS(═O)_(p)NR¹²R¹²;

R¹¹, at each occurrence, is independently selected from H, halogen, C₁₋₅alkyl, —(CH₂)_(n)—OH, C₃₋₆ cycloalkyl, and phenyl;

R¹², at each occurrence, is independently selected from H, C₁₋₅ alkyl,C₃₋₆ cycloalkyl, phenyl, and heterocyclyl, or R¹² and R¹² together withthe nitrogen atom to which they are both attached form a heterocyclicring optionally substituted with C₁₋₄alkyl;

n, at each occurrence, is an integer independently selected from 0, 1,and 2; and

p, at each occurrence, is an integer independently selected from 0, 1,and 2.

In another aspect, the present invention provides compounds of Formula(IVb):

or stereoisomers, tautomers, pharmaceutically acceptable salts,solvates, or prodrugs thereof, wherein:

ring A is independently selected from

R¹ and R² are independently selected from H, F, C₁₋₄ alkyl, and OH;

R^(1a), at each occurrence, is independently selected from H, F, CH₃,and OH;

R³ is independently selected from H, F, Cl, Br, I, C₂₋₄alkenyl(optionally substituted C(═O)OH), CN, and —(CH₂)_(n)—OH;

R⁴ is independently selected from H, OH, F, OC₁₋₄ alkyl, C₁₋₄ alkyl, CN,C₃₋₆ cycloalkyl, aryl, and 5- to 6-membered heterocyclyl, wherein saidcycloalkyl, aryl and heterocyclyl are optionally substituted with R⁶;

R⁶ is independently selected from OH, NH₂, halogen, C₁₋₆ alkyl, C₃₋₆cycloalkyl, —(CH₂)_(n)—C(═O)OH, —(CH₂)_(n)—C(═O)OC₁₋₄ alkyl,—(CH₂)_(n)—OC₁₋₄ alkyl, ═O, C₃₋₆ cycloalkyl, 4- to 10-memberedheterocyclyl, and —O-4- to 10-membered heterocyclyl, wherein saidcycloalkyl and heterocyclyl are optionally substituted with R¹⁰;

R^(8a) is independently selected from H, F, Cl, Br, CN, OCH₃, OCF₃, CH₃,C(═O)CH₃, CF₃, OCHF₂, NHC(═O)C₁₋₄ alkyl, aryl, C₃₋₆ cycloalkyl, and 4-to 12-membered heterocyclyl, wherein said aryl, cycloalkyl, andheterocyclyl are optionally substituted with R¹⁰;

R^(8b) is independently selected from H and F;

R^(8c) is independently selected from H, F, Cl, CH₃, and OCH₃;

R¹⁰ is independently selected from C₁₋₆ alkyl, —C₃₋₆ cycloalkyl, F, Cl,Br, CF₃, CHF₂, CN, and OC₁₋₅ alkyl; and

n, at each occurrence, is an integer independently selected from 0, 1,and 2.

In another aspect, the present invention provides compounds of Formula(IIb), or stereoisomers, tautomers, pharmaceutically acceptable saltssolvates, or prodrugs thereof, wherein:

ring A is independently selected from

ring B is independently selected from

W is independently selected from CHR^(1a), O, NH, and N(C₁₋₄ alkyl);

R¹ is independently selected from H and C₁₋₄ alkyl;

R^(1a) is independently selected from H F, CH₃, and hydroxyl;

R² is independently selected from H and hydroxyl;

R³ is independently selected from H, ═O, F, CHF₂, CF₃, OCF₃, OCHF₂, CH₃,CN, —(CH₂)₀₋₂—OH, OC₁₋₄ alkyl, C(═O)C₁₋₄ alkyl, —(CH₂)₀₋₁—C(═O)OH,—C(═O)OC₁₋₄ alkyl, —S(═O)₂C₁₋₄ alkyl, and —NHC(═O)OC₁₋₄ alkyl;

R^(3c) is independently selected from H, CF₂H, CF₃, C₁₋₄ alkyl, and CD₃;

R⁴ is independently selected from H and F;

R^(8b) is independently selected from H and F;

R^(8c) is independently selected from H and Cl;

R¹⁰ is independently selected from H, C₁₋₆ alkyl (optionally substitutedwith R¹¹), aryl, —(CH₂)_(n)—C₃₋₆ cycloalkyl (optionally substituted withR¹¹), —(CH₂)_(n)—O-4- to 10-membered heterocyclyl, F, Cl, Br, CN,C(═O)NR¹²R¹², Si(C₁₋₄ alkyl)₃, and —(CH₂)_(n)—OR¹²;

R¹¹, at each occurrence, is independently selected from H, halogen, andC₁₋₅ alkyl; and

n, at each occurrence, is an integer independently selected from 0, 1,2, 3, and 4; and

other variables are as defined in Formula (IVb) above.

In another aspect, the present invention provides compounds of Formula(IIc), or stereoisomers, tautomers, pharmaceutically acceptable salts,solvates, or prodrugs thereof, wherein:

ring A is independently selected from

ring B is independently selected from,

W is independently selected from CHR^(1a), O, NH, and N(C₁₋₄ alkyl);

R¹ is independently selected from H and C₁₋₄ alkyl;

R^(1a) is independently selected from H F, CH₃, and hydroxyl;

R² is independently selected from H and hydroxyl;

R³ is independently selected from H, ═O, F, CHF₂, CF₃, OCF₃, OCHF₂, CH₃,CN, —(CH₂)₀₋₂—OH, OC₁₋₄ alkyl, C(═O)C₁₋₄ alkyl, —(CH₂)₀₋₁—C(═O)OH,—C(═O)OC₁₋₄ alkyl, —S(═O)₂C₁₋₄ alkyl, and —NHC(═O)OC₁₋₄ alkyl;

R^(3c) is independently selected from H, CF₂H, CF₃, C₁₋₄ alkyl, and CD₃;

R⁴ is independently selected from H and F;

R^(8b) is independently selected from H and F;

R^(8c) is independently selected from H and Cl;

R¹⁰ is independently selected from H, C₁₋₆ alkyl (optionally substitutedwith R¹¹), aryl, —(CH₂)_(n)—C₃₋₆ cycloalkyl (optionally substituted withR¹¹), —(CH₂)_(n)—O-4- to 10-membered heterocyclyl, F, Cl, Br, CN,C(═O)NR¹²R¹², Si(C₁₋₄ alkyl)₃, and —(CH₂)_(n)—OR¹²;

R¹¹, at each occurrence, is independently selected from H, halogen, andC₁₋₅ alkyl; and

n, at each occurrence, is an integer independently selected from 0, 1,2, 3, and 4; and

other variables are as defined in Formula (IIc) above.

In another aspect, the present invention provides compounds of Formula(IIa), or stereoisomers, tautomers, pharmaceutically acceptable salts,solvates, or prodrugs thereof, wherein:

ring A is independently selected from

ring B is independently selected from

G¹ is independently selected from

W is independently selected from CHR¹, O, NH, and N(C₁₋₄ alkyl);

Y is independently selected from —NH—, —NHC(═O)— and —C(═O)NH—;

R¹ and R² are independently selected from H, F, C₁₋₄ alkyl, andhydroxyl;

R³ is independently selected from H, ═O, F, CHF₂, CF₃, OCF₃, OCHF₂, CH₃,CN, —(CH₂)₀₋₂—OH, OC₁₋₄ alkyl, C(═O)C₁₋₄ alkyl, —(CH₂)₀₋₁—C(═O)OH,—C(═O)OC₁₋₄ alkyl, —S(═O)₂C₁₋₄ alkyl, and —NHC(═O)OC₁₋₄ alkyl;

R^(3c) is independently selected from H, CF₂H, CF₃, C₁₋₄ alkyl, and CD₃;

R⁴ is independently selected from H, F, and C₁₋₄ alkyl; and

R⁷ is H; and

other variables are as defined in Formula (IIa) above.

In another aspect, the present invention provides compounds of Formula(V):

or stereoisomers, tautomers, pharmaceutically acceptable salts,solvates, or prodrugs thereof, wherein:

ring A is independently selected from phenyl and a 5- to 6-memberedheterocyclyl;

W is independently selected from CHR^(1a), O, NH, and N(C₁₋₄ alkyl);

R¹ is independently selected from H and C₁₋₄ alkyl;

R^(1a) is independently selected from H and F;

R² is independently selected from H and hydroxyl;

R³ is independently selected from H, haloalkyl, and C₁₋₄alkyl(optionally substituted with R⁶), F, CN, C(═O)C₁₋₄ alkyl, C(═O)OH,—S(═O)₂C₁₋₄alkyl, and —NHC(═O)OC₁₋₄ alkyl;

R⁴ is independently selected from H, OH, F, Cl, Br, C₁₋₄ alkyl, C₁₋₄alkoxy, CF₃, and CN;

R⁵ is independently selected from H, C₁₋₄ alkyl (optionally substitutedwith halogen, hydroxyl, alkoxy, carboxy, alkoxycarbonyl, amino,substituted amino), —(CH₂)_(n)—C₃₋₁₀ carbocyclyl and —(CH₂)_(n)-4- to10-membered heterocyclyl, wherein said carbocyclyl and heterocyclyl areoptionally substituted with R⁶;

R⁶ is independently selected from —(CH₂)_(n)—OH, ═O, NH₂, —(CH₂)_(n)—CN,halogen, C₁₋₆ alkyl, —(CH₂)_(n)—C(═O)OH, —(CH₂)_(n)—C(═O)OC₁₋₄ alkyl,—(CH₂)_(n)—OC₁₋₄ alkyl, —(CH₂)_(n)—C₃₋₆ cycloalkyl, —(CH₂)_(n)-4- to10-membered heterocyclyl, and —O—(CH₂)_(n)-4- to 10-memberedheterocyclyl, wherein said cycloalkyl and heterocyclyl are optionallysubstituted with R¹⁰;

R⁷ is independently selected from H, F, Cl, and methyl;

R^(8b) is independently selected from H and F;

R^(8c) is independently selected from H, F, Cl, CH₃, and OCH₃;

R¹⁰ is independently selected from H, C₁₋₆ alkyl (optionally substitutedwith R¹¹), C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, —(CH₂)_(n)—C₃₋₆ cycloalkyl(optionally substituted with R¹¹), —(CH₂)_(n)—O-4- to 10-memberedheterocyclyl (optionally substituted with R¹¹), F, Cl, Br, CN, NO₂, ═O,C(═O)NR¹²R¹², C(═O)OR¹², Si(C₁₋₄ alkyl)₃, —(CH₂)_(n)—OR¹², and—(CH₂)_(n)—NR¹²R¹²;

R¹¹, at each occurrence, is independently selected from H, halogen, C₁₋₅alkyl, —(CH₂)_(n)—OH, C₃₋₆ cycloalkyl, and phenyl;

R¹², at each occurrence, is independently selected from H, C₁₋₅ alkyl,C₃₋₆ cycloalkyl, phenyl, and heterocyclyl, or R¹² and R¹² together withthe nitrogen atom to which they are both attached form a heterocyclicring optionally substituted with C₁₋₄alkyl; and

n, at each occurrence, is an integer independently selected from 0, 1,and 2; and

p, at each occurrence, is an integer independently selected from 0, 1,and 2.

In another aspect, the present invention provides compounds of Formula(VI):

or stereoisomers, tautomers, pharmaceutically acceptable salts,solvates, or prodrugs thereof, wherein:

ring A is independently selected from phenyl and a 5- to 6-memberedheterocyclyl;

W is independently selected from (CR¹R²)₁₋₂, O, NH, and N(C₁₋₄ alkyl);

Y is independently selected from —NH—, —NHC(═O)— and —C(═O)NH—;

R¹ and R² are independently selected from H, halogen, CF₃, C₁₋₆ alkyl,and hydroxyl;

R^(3c) is independently selected from H, haloalkyl, and C₁₋₄alkyl(optionally substituted with R⁶), —(CH₂)₁₋₂—OH, C(═O)C₁₋₄ alkyl,—(CH₂)₀₋₂—C(═O)OH, and —C(═O)OC₁₋₄ alkyl; only one R^(3c) is present onthe ring;

R⁴ is independently selected from H, OH, F, Cl, Br, C₁₋₄ alkyl, C₁₋₄alkoxy, CF₃, CN, C₃₋₆ cycloalkyl, aryl, and 5- to 6-memberedheterocyclyl, wherein said cycloalkyl, aryl and heterocyclyl areoptionally substituted with R⁶;

R⁵ is independently selected from H, C₁₋₄ alkyl (optionally substitutedwith halogen, hydroxyl, alkoxy, carboxy, alkoxycarbonyl, amino,substituted amino), —(CH₂)_(n)—C₃₋₁₀ carbocyclyl and —(CH₂)_(n)-4- to10-membered heterocyclyl, wherein said carbocyclyl and heterocyclyl areoptionally substituted with R⁶;

R⁶ is independently selected from —(CH₂)_(n)—OH, ═O, NH₂, —(CH₂)_(n)—CN,halogen, C₁₋₆ alkyl, —(CH₂)_(n)—C(═O)OH, —(CH₂)_(n)—C(═O)OC₁₋₄ alkyl,—(CH₂)_(n)—OC₁₋₄ alkyl, —(CH₂)_(n)—C₃₋₆ cycloalkyl, —(CH₂)_(n)-4- to10-membered heterocyclyl, and —O—(CH₂)_(n)-4- to 10-memberedheterocyclyl, wherein said cycloalkyl and heterocyclyl are optionallysubstituted with R¹⁰;

R⁷ is independently selected from H, F, and methyl;

R^(8a) is independently selected from H, F, Cl, Br, CN, OCH₃, OCF₃, CH₃,C(═O)CH₃, CHF₂, CF₃, CCH₃F₂, OCHF₂, aryl, C₃₋₆ cycloalkyl, and 4- to6-membered heterocyclyl optionally substituted with R¹⁰;

R^(8b) is independently selected from H and F;

R^(8c) is independently selected from H, F, Cl, CH₃, and OCH₃;

R¹⁰ is independently selected from H, C₁₋₆ alkyl (optionally substitutedwith R¹¹), C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, —(CH₂)_(n)—C₃₋₆ cycloalkyl(optionally substituted with R¹¹), —(CH₂)_(n)—O-4- to 10-memberedheterocyclyl (optionally substituted with R¹¹), F, Cl, Br, CN, NO₂, ═O,CONR¹²R¹², C(═O)OR¹², Si(C₁₋₄ alkyl)₃, —(CH₂)_(n)—OR¹², and—(CH₂)_(n)—NR¹²R¹²;

R¹¹, at each occurrence, is independently selected from H, halogen, C₁₋₅alkyl, —(CH₂)_(n)—OH, C₃₋₆ cycloalkyl, and phenyl;

R¹², at each occurrence, is independently selected from H, C₁₋₅ alkyl,C₃₋₆ cycloalkyl, phenyl, and heterocyclyl, or R¹² and R¹² together withthe nitrogen atom to which they are both attached form a heterocyclicring optionally substituted with C₁₋₄alkyl;

n, at each occurrence, is an integer independently selected from 0, 1,and 2; and

p, at each occurrence, is an integer independently selected from 0, 1,and 2.

In another aspect, the present invention provides compounds of Formula(VII):

or stereoisomers, tautomers, pharmaceutically acceptable salts,solvates, or prodrugs thereof, wherein:

ring A is independently selected from

ring B is independently selected from

R¹ is independently selected from H and C₁₋₄ alkyl;

R¹⁰ is independently selected from F, Cl, CF₃, CHF₂, and COOH;

R^(3c) is independently selected from H, CHF₂, CD₃, CH₃, and

R^(8b) is independently selected from H and F; and

R^(8c) is independently selected from H, F, Cl, CH₃, and OCH₃.

In another aspect, the present invention provides compounds of Formula(VII), or stereoisomers, tautomers, pharmaceutically acceptable salts,solvates, or prodrugs thereof, wherein:

ring A is independently selected from

ring B is independently selected from

R¹ is independently selected from H and C₁₋₄ alkyl;

R¹⁰ is independently selected from F, Cl, CF₃, CHF₂, and COOH;

R^(3c) is independently selected from H, CHF₂, CD₃, and CH₃;

R^(8b) is independently selected from H and F; and

R^(8c) is independently selected from H, F, Cl, CH₃, and OCH₃.

In another aspect, the present invention provides compounds of Formula(VIII):

or stereoisomers, tautomers, pharmaceutically acceptable salts,solvates, or prodrugs thereof, wherein:

R¹ is C₁₋₄ alkyl;

R¹⁰ is independently selected from F, Cl, CF₃, CHF₂ and COOH;

R^(3c) is independently selected from CHF₂, CD₃, and CH₃;

R^(8b) is H; and

R^(8c) is independently selected from F and Cl.

In another aspect, the present invention provides compounds of Formula(VIII), or stereoisomers, tautomers, pharmaceutically acceptable salts,solvates, or prodrugs thereof, wherein:

R¹ is C₁₋₄ alkyl;

R¹⁰ is independently selected from F, Cl, CF₃, CHF₂ and COOH;

R^(3c) is independently selected from CHF₂, CD₃, and CH₃;

R^(8b) is H; and

R^(8c) is independently selected from F and Cl.

In another aspect, the present invention provides compounds of Formula(IX):

or stereoisomers, tautomers, pharmaceutically acceptable salts,solvates, or prodrugs thereof, wherein:

R¹ is C₁₋₄ alkyl;

R¹⁰ is independently selected from F, Cl, CF₃, CHF₂, and COOH;

R^(3c) is independently selected from CHF₂, CD₃, and CH₃;

R^(8b) is H; and

R^(8c) is independently selected from F and Cl.

In another aspect, the present invention provides compounds of Formula(IX), or stereoisomers, tautomers, pharmaceutically acceptable salts,solvates, or prodrugs thereof, wherein:

R¹ is C₁₋₄ alkyl;

R¹⁰ is independently selected from F, Cl, CF₃, CHF₂, and COOH;

R^(3c) is independently selected from CHF₂, CD₃, and CH₃;

R^(8b) is H; and

R^(8c) is independently selected from F and Cl.

In another aspect, the present invention provides compounds of Formula(X):

or stereoisomers, tautomers, pharmaceutically acceptable salts,solvates, or prodrugs thereof, wherein:

R¹⁰ is independently selected from F, Cl, CF₃, CHF₂, and COOH; and

R^(3c) is independently selected from CHF₂, CD₃, and CH₃.

In another aspect, the present invention provides compounds of Formula(VII), or stereoisomers, tautomers, pharmaceutically acceptable salts,solvates, or prodrugs thereof, wherein:

ring A is independently selected from

ring B is

R¹ is independently selected from H and C₁₋₄ alkyl;

R¹⁰ is COOH;

R^(3c) is independently selected from H, CHF₂, CD₃, and CH₃;

R^(8b) is independently selected from H and F; and

R^(8c) is independently selected from H, F, Cl, CH₃, and OCH₃.

In another aspect, the present invention provides compounds selectedfrom

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt,solvates, or prodrugs thereof.

In one embodiment, G¹ is independently selected from the groupconsisting of

wherein R⁸ is, independently at each occurrence, selected from the groupconsisting of H, halogen, CN, C₁₋₆ alkyl, haloalkyl, alkoxy, haloalkoxy,and 4- to 6-membered heterocyclyl.

In another embodiment, G¹ is

wherein R⁸ is, independently at each occurrence, selected from the groupconsisting of H, halogen, CN, methyl, ethyl, CF₃ CHF₂, OMe, OEt, OCF₃,OCHF₂, aryl, C₃₋₆ cycloalkyl, and 4- to 6-membered heterocyclyl.

In another embodiment, G¹ is

and selected from the group consisting of

In another embodiment, G¹ is

wherein R^(8a) is independentlyselected from the group consisting of H, F, OCH₃, OCHF₂, and

In another embodiment, R^(8b) is independently selected from the groupconsisting of H, F and Cl.

In another embodiment, R^(8b) is independently selected from the groupconsisting of H and F.

In another embodiment, R^(8c) is Cl.

In another embodiment, G¹ is

selected from the group consisting

In embodiment, G¹ is

In one embodiment, the present invention provides compounds of Formulae(I), (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIIa),(IIIb), (IVb), (V), and (VI) or stereoisomers, tautomers,pharmaceutically acceptable salts, solvates, or prodrugs thereof,wherein ring A is independently selected from the group consisting ofimidazole, oxadiazole, pyridine, pyridinone, pyridazine, pyridazinone,and phenyl.

In another embodiment

is independently selected from the group consisting of

In another embodiment,

is independently selected from the group consisting of

In another embodiment,

is independently selected from the group consisting of

In still another embodiment,

is independently selected from the group consisting of

In another embodiment,

In another embodiment,

In another embodiment,

In another embodiment

In another embodiment

In another embodiment

In another embodiment

In another embodiment, ring B is independently selected from

In another embodiment, ring B is independently selected from z,

In another embodiment, ring B is independently selected from,

In another embodiment, ring B is

wherein R^(3c) is independently selected from H, CHF₂, CD₃, CH₃, andSO₂CH₃.

In another embodiment, R¹ is independently selected from the groupconsisting of H, OH, F, and C₁₋₄ alkyl.

In another embodiment, R¹ is independently selected from the groupconsisting of H and C₁₋₄ alkyl.

In another embodiment, R¹ is independently selected from the groupconsisting of H and methyl, ethyl, and isopropyl.

In one embodiment, R² is, independently at each occurrence, selectedfrom the group consisting of H and C₁₋₄ alkyl.

In another embodiment, R² is, independently at each occurrence, selectedfrom the group consisting of H and methyl.

In another embodiment, one of R¹ and R² is H and the other is methyl;

In another embodiment, R¹ and R² together are ═O;

In one embodiment, Ring B is 5-membered heteroaryl comprising carbonatoms and heteroatoms selected from N and NR^(3c); R³ is independentlyselected from H, halogen, C₁₋₄ alkyl (optionally substituted with R⁶),CN, —(CH₂)_(n)—OR⁵, —(CH₂)_(n)—NR⁵R⁵, —(CH₂)_(n)—C(═O)R⁵, and—(CH₂)_(n)—C(═O)OR; R^(3c) is independently selected from H, haloalkyl,C₁₋₄ alkyl (optionally substituted with R⁶), —(CH₂)₁₋₂—OH, C(═O)C₁₋₄alkyl, —(CH₂)₁₋₂—C(═O)OH, —C(═O)OC₁₋₄ alkyl, S(═O)_(p)C₁₋₆ alkyl,—(CH₂)_(n)—C₃₋₁₀ carbocyclyl and —(CH₂)_(n)-4- to 10-memberedheterocyclyl, wherein said carbocyclyl and heterocyclyl are optionallysubstituted with R⁶; R⁵ is independently selected from H, C₁₋₄ alkyl(optionally substituted with halogen, hydroxyl, alkoxy, carboxy,alkoxycarbonyl), —(CH₂)_(n)—C₃₋₁₀ carbocyclyl and —(CH₂)_(n)-4- to10-membered heterocyclyl, wherein said carbocyclyl and heterocyclyl areoptionally substituted with R⁶; R⁶ is independently selected from OH,═O, —(CH₂)_(n)NH₂, —(CH₂)_(n)CN, halogen, C₁₋₆ alkyl,—(CH₂)_(n)—C(═O)OH, —(CH₂)_(n)—C(═O)OC₁₋₄ alkyl, —(CH₂)_(n)—OC₁₋₄ alkyl,—(CH₂)_(n)—C₃₋₁₀ carbocyclyl, —(CH₂)_(n)-4- to 10-membered heterocyclyl,and —(CH₂)_(n)-4- to 10-membered heterocyclyl, wherein said carbocyclyland heterocyclyl are optionally substituted with R¹⁰.

In another aspect, the present invention provides a compound selectedfrom any subset list of compounds exemplified in the presentapplication.

In another aspect, the present invention provides a compound selectedfrom:

-   (9R,13S)-13-(4-{5-chloro-2-[(pyrimidin-2-yl)amino]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one;-   ethyl    2-[4-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)-1H-pyrazol-1-yl]acetate;-   2-[4-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)-1H-pyrazol-1-yl]acetic    acid;-   2-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)acetonitrile;-   (9R,13S)-13-{4-[5-chloro-2-(1-methyl-1H-pyrazol-4-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one;-   (9R,13S)-13-{4-[5-chloro-2-(1,3-dimethyl-1H-pyrazol-4-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one    trifluoroacetate;-   (10R,14S)-14-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-10-methyl-4,5,8-triazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-9-one;-   1-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)-1H-pyrazole-4-carboxylic    acid;-   (9R,13S)-13-[4-(2-bromo-5-chlorophenyl)-5-chloro-6-oxo-1,6-dihydropyrimidin-1-yl]-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one;-   (9R,13S)-13-{4-[3-chloro-2-fluoro-6-(1,3-thiazol-5-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one;-   (9R,13S)-13-{4-[3-chloro-2-fluoro-6-(1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one    trifluoroacetate;-   (9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one    trifluoroacetate;-   (9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-9-ethyl-3-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one    trifluoroacetate;-   (9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-methyl-9-(propan-2-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one    trifluoroacetate;-   (9S,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-methyl-9-(propan-2-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one    trifluoroacetate;-   (9S,13S)-13-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-methyl-9-(propan-2-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one    trifluoroacetate;-   (9R,13S)-13-{4-[3-chloro-6-(difluoromethyl)-2-fluorophenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one    trifluoroacetate;-   (9R,13S)-13-{4-[3-chloro-6-(1,1-difluoroethyl)-2-fluorophenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one    trifluoroacetate;-   (9R,13S)-13-{4-[3-chloro-2-fluoro-6-(1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-16-fluoro-3,9-dimethyl-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one;-   (9R,13S)-13-[4-(3-chloro-2,6-difluorophenyl)-6-oxo-1,6-dihydropyrimidin-1-yl]-16-fluoro-3,9-dimethyl-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one;-   (9R,13S)-13-{4-[3-chloro-2-fluoro-6-(1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one;-   (9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one;-   (9R)-13-{4-[3-chloro-2-fluoro-6-(1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one;-   (9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(²H₃)methyl-9-methyl-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one;-   (10R,14S)-14-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-10-methyl-3,8-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-9-one    trifluoroacetate;-   1-(4-chloro-2-{1-[(9R,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}-3-fluorophenyl)-1H-1,2,3-triazole-4-carbonitrile;-   (9R,13S)-13-(4-{5-chloro-2-[4-(difluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one;-   (9R,13S)-13-(4-{5-chloro-2-[4-(difluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(²H₃)methyl-9-methyl-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one;-   1-(4-chloro-3-fluoro-2-{1-[(9R,13S)-3-(²H₃)methyl-9-methyl-8-oxo-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)-1H-1,2,3-triazole-4-carbonitrile;-   1-(4-chloro-2-{1-[(9R,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)-1H-1,2,3-triazole-4-carbonitrile;-   (9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one;-   (10R,14S)-14-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-10-methyl-3,8-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-9-one;-   (9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,17-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one;-   (9R,13S)-13-{4-[2-(4-bromo-1H-1,2,3-triazol-1-yl)-5-chlorophenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(²H₃)methyl-9-methyl-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one;-   (9R,13S)-13-(4-{5-chloro-2-[4-(pyrimidin-2-yl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(²H₃)methyl-9-methyl-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one;-   (10R,14S)-14-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-4,10-dimethyl-3,8-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-9-one;-   (10R,14S)-14-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-5-methoxy-10-methyl-3,8-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-9-one;-   (10R,14S)-5-chloro-14-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-10-methyl-3,8-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-9-one;-   (9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,16-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one;-   (9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaene-16-carboxamide;-   1-(4-chloro-2-{1-[(9R,13S)-3-(²H₃)methyl-9-methyl-8-oxo-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)-1H-1,2,3-triazole-4-carboxamide;-   (9R,13S)-13-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one;-   (9R,13S)-13-{4-[3-chloro-2-fluoro-6-(1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one    trifluoroacetate;-   (9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one    trifluoroacetate;-   (9R,13S)-13-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one;    trifluoroacetate;-   (9R,13S)-13-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(2-hydroxyethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one    trifluoroacetate;-   (9R,13S)-13-(4-{5-chloro-2-[4-(difluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(2-hydroxyethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one    trifluoroacetate;-   (9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(2-hydroxyethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one    trifluoroacetate;-   (9R,13S)-13-{4-[5-chloro-2-(1H-1,2,3,4-tetrazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(2-hydroxyethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one    trifluoroacetate;-   (9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(2-hydroxyethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one    trifluoroacetate;-   2-[(9R,13S)-13-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-3-yl]acetic    acid trifluoroacetate;-   2-[(9R,13S)-13-(4-{5-chloro-2-[4-(difluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-3-yl]acetic    acid trifluoroacetate;-   2-[(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-3-yl]acetic    acid trifluoroacetate;-   2-[(9R,13S)-13-{4-[5-chloro-2-(1H-1,2,3,4-tetrazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-3-yl]acetic    acid trifluoroacetate;-   2-[(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-3-yl]acetic    acid trifluoroacetate;-   (9R,13S)-13-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one    trifluoroacetate;-   (9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one    trifluoroacetate;-   methyl    (9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-8-oxo-2,3,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),3,5,14,16-pentaene-4-carboxylate    trifluoroacetate;-   methyl    (9R,13)-13-(4-{5-chloro-2-[4-(difluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-9-methyl-8-oxo-2,3,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),3,5,14,16-pentaene-4-carboxylate    trifluoroacetate;-   (9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-8-oxo-2,3,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),3,5,14,16-pentaene-4-carboxylic    acid trifluoroacetate;-   (9R,13S)-13-(4-{5-chloro-2-[4-(difluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-9-methyl-8-oxo-2,3,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),3,5,14,16-pentaene-4-carboxylic    acid trifluoroacetate;-   (9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(²H₃)methyl-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one    trifluoroacetate;-   (9R,13S)-13-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(²H₃)methyl-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one    trifluoroacetate;-   (9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one;-   (9R,13S)-13-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one;-   (9R,13S)-13-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl(10,11-²H₂)-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one    trifluoroacetate;-   (9R,13S)-13-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(²H₃)methyl-9-methyl(10,11-²H₂)-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one    trifluoroacetate;-   (9R,13S)-13-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl(10,11-²H₂)-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one    trifluoroacetate;-   (9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl(10,11-²H₂)-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one    trifluoroacetate;-   (10R,14S)-14-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-10-methyl-3,8,16-triazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-9-one,    bis-trifluoroacetate;-   (9R,13S)-13-[4-(5-chloro-1-methyl-1H-indazol-7-yl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3-(²H₃)methyl-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one    trifluoroacetate;-   (9R,13S)-13-{4-[5-chloro-2-(1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one;-   (9R,13S)-13-[4-(5-chloro-1-methyl-1H-indazol-7-yl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3-(difluoromethyl)-9-methyl-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one;-   (10R,14S)-14-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-10-methyl-3,8,16-triazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-9-one    bis-trifluoroacetate;-   (9R,13S)-3-(difluoromethyl)-9-methyl-13-(4-{5-methyl-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,4,7,17-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one;-   (9R,13S)-13-{4-[5-chloro-2-(1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-5-(trifluoromethyl)-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one;-   (10R,14S)-14-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-10-methyl-3,8,16-triazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-9-one,    bis-trifluoroacetate;-   (9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,16-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one;-   6-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-3-[(9R,13S)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-3,4-dihydropyrimidin-4-one;-   (9S,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-10-fluoro-9-methyl-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one;-   (9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-11-fluoro-9-methyl-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one;-   (9S,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-10,16-difluoro-3,9-dimethyl-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one;-   (9S,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-10,16-difluoro-3,9-dimethyl-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one;-   (9R,13S)-13-{4-[5-chloro-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(Â²Hâ,f)methyl-9-methyl-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one;-   6-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-3-[(9R,13S)-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-3,4-dihydropyrimidin-4-one;-   (9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaene-16-carbonitrile;-   (9R,13S)-13-(4-{5-chloro-2-[4-(trimethylsilyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one    trifluoroacetate;-   (9R,13S)-13-[4-(3-chloro-2,6-difluorophenyl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one    trifluoroacetate;-   (9R,13S)-13-{4-[5-chloro-2-(1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one    trifluoroacetate;-   (13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one    trifluoroacetate;-   (9S,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one;-   (9R,13S)-13-{4-[5-chloro-2-(4-methyl-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one    trifluoroacetate;-   (9R,13S)-3-(difluoromethyl)-9-methyl-13-(4-{5-methyl-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one;-   (9R,13S)-13-[4-(2-bromo-5-chlorophenyl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one;-   (9R,13S)-13-{4-[3-chloro-2-fluoro-6-(4-methyl-H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one;-   (9R,13S)-13-(4-{5-chloro-2-[1-(difluoromethyl)-1H-pyrazol-4-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one;-   (9R,13S)-13-[4-(3-fluoro-4-methylpyridin-2-yl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one;-   (9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,17-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one;-   (9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one    trifluoroacetate;-   (9R,13S)-13-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one    trifluoroacetate;-   (9R,13S)-13-{4-[2-(4-bromo-1H-1,2,3-triazol-1-yl)-5-chlorophenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one    trifluoroacetate;-   1-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)-1H-1,2,3-triazole-4-carboxamide    trifluoroacetate;-   1-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)-1H-1,2,3-triazole-4-carbonitrile    trifluoro acetate;-   (10R,14S)-14-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-10-methyl-9-oxo-3,8-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1    (19),2(7),3,5,15,17-hexaene-5-carbonitrile;-   (9R,13S)-13-(4-{5-chloro-2-[4-({3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy}methyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one    trifluoroacetate;-   (9R,13S)-13-(4-{5-chloro-2-[4-(hydroxylmethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one    trifluoroacetate;-   (9R,13S)-13-(4-{5-chloro-2-[4-(difluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one    trifluoroacetate;-   (9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one    trifluoroacetate;-   (9R,13S)-13-(4-{5-chloro-2-[4-(fluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one    trifluoroacetate;-   1-(4-chloro-2-{1-[(9R,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)-1H-1,2,3-triazole-4-carbonitrile    trifluoroacetate;-   (9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(²H₃)methyl-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one    trifluoroacetate;-   (9R,13S)-13-(4-{5-chloro-2-[4-(difluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one    trifluoroacetate;-   (9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one    trifluoroacetate;-   (9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(²H₃)methyl-9-methyl-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one    trifluoroacetate;-   (9S,13R)-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one;-   (9R,13R)-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one;-   (9R,13S)-13-{4-[5-chloro-2-(pyridin-3-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one;-   (9R,13S)-13-(4-{5-chloro-2-[4-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one;-   (9R,13S)-3-(difluoromethyl)-9-methyl-13-(6-oxo-4-{2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-1,6-dihydropyrimidin-1-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one;-   (9R,13S)-3-(difluoromethyl)-13-(4-{5-fluoro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one;-   (9R,13S)-13-{4-[5-chloro-2-(4-hydroxy-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one    trifluoroacetate;-   5-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)pyridine-3-carbonitrile;-   (9R,13S)-13-{4-[5-chloro-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one    trifluoroacetate;-   methyl    4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}benzoate;-   (9R,13S)-13-{4-[3-chloro-6-(4-ethoxy-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one    trifluoroacetate;-   (9R,13S)-13-{4-[3-chloro-6-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one    trifluoroacetate;-   (9R,13S)-13-{4-[3-chloro-2-fluoro-6-(trifluoromethyl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one    trifluoroacetate;-   (9R,13S)-13-{4-[3-chloro-6-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(²H₃)methyl-9-methyl-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one;-   (9R,13S)-13-(4-{3-chloro-2-fluoro-6-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one    trifluoroacetate;-   1-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}-3-fluorophenyl)-1H-1,2,3-triazole-4-carbonitrile    trifluoroacetate;-   (9R,13S)-13-(4-{3-chloro-2-fluoro-6-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(²H₃)methyl-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one    trifluoroacetate;-   1-(4-chloro-2-{1-[(9R,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}-3-fluorophenyl)-1H-1,2,3-triazole-4-carbonitrile    trifluoroacetate;-   (9R,13S)-13-{4-[3-chloro-6-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one    trifluoroacetate;-   (9R,13S)-13-(4-{3-chloro-6-[4-(difluoromethyl)-1H-1,2,3-triazol-1-yl]-2-fluorophenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one    trifluoroacetate;-   (9R,13S)-13-(4-{3-chloro-6-[4-(difluoromethyl)-1H-1,2,3-triazol-1-yl]-2-fluorophenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one    trifluoroacetate;-   (9R,13S)-13-[4-(3-chlorophenyl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one;-   4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}benzoic    acid;-   (9R,13S)-3-(difluoromethyl)-9-methyl-13-{6-oxo-4-[5-(propan-2-yl)-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl]-1,6-dihydropyrimidin-1-yl}-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one;-   (9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(²H₃)methyl-9-methyl-3,4,7,17-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one;-   (9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaene-16-carbonitrile;-   (9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,17-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one;-   (9S,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-10-fluoro-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one    trifluoroacetate;-   (9R,13S)-3-(difluoromethyl)-13-(4-{5-ethyl-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one;-   (9S,13S)-13-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-10-fluoro-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one    trifluoroacetate;-   (9R,13S)-13-{5-chloro-4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one    trifluoroacetate;-   (9R,13S)-3-(difluoromethyl)-13-(4-{4-fluoro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one;-   (9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(²H₃)methyl-9-methyl-3,4,7,17-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one;-   (9R,13S)-13-[4-(3-chloro-2,6-difluorophenyl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one;-   (9R,13S)-13-[4-(5-chloro-2-phenylphenyl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one;-   (9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-3,4,7,16-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one;-   (9R,13S)-13-[4-(5-chloro-1-ethyl-1H-indazol-7-yl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one;-   (9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one;-   (9R,13S)-13-{4-[3-chloro-2-fluoro-6-(1H-1,2,3,4-tetrazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one    trifluoroacetate;-   (9R,13S)-13-{4-[3-chloro-2-fluoro-6-(1H-1,2,3,4-tetrazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one    trifluoroacetate;-   (9R,13S)-13-{4-[5-chloro-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one;-   (9R,13S)-13-{4-[5-chloro-2-(1H-1,2,3,4-tetrazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one    trifluoroacetate;-   (9R,13S)-13-{4-[5-chloro-2-(1H-1,2,3,4-tetrazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one;-   (9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-5-fluoro-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one;-   (9R,13S)-13-{5-bromo-4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one;-   (9R,13S)-13-(4-{5-chloro-3-fluoro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one;-   (10R,14S)-14-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-10-methyl-5,8-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-9-one;-   (10R,14S)-14-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-10-methyl-5,8-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-9-one;-   (9R,13S)-13-[4-(6-chloro-1H-1,3-benzodiazol-4-yl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one;-   methyl    4-[(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1    (18),2,5,14,16-pentaen-4-yl]piperidine-1-carboxylate;-   (9R,13S)-13-(4-{4-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one;-   (9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-5-methyl-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one;-   (9R,13S)-13-[4-(5-chloro-2-iodophenyl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one;-   (9R,13S)-13-{4-[3-chloro-2-fluoro-6-(4-phenyl-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one    trifluoroacetate;-   N-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}-3-fluorophenyl)carbamate    trifluoroacetate;-   (9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-15-ium-15-olate;-   (9R,13S)-13-(4-{5-chloro-2-[4-(pyridin-3-yl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one    trifluoroacetate;-   (9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-4-(pyridin-3-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2,5,14,16-pentaen-8-one;-   (9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-3-(pyridin-3-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one;-   (9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-3-phenyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one;-   (9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]pyridin-3-yl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one;-   (9R,13S)-13-(5-bromo-4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]pyridin-3-yl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one;-   (9R,13S)-13-(4-{5-chloro-4-fluoro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one;-   (9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-9-methyl-3-phenyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one;-   (9R,13S)-13-(4-{4,5-Dichloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one;-   (9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-4-(1-methyl-1H-imidazol-5-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2,5,14,16-pentaen-8-one;-   4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}-N-(2,2,2-trifluoroethyl)benzamide;-   (9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-5,9-dimethyl-4,5,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),3,14,16-pentaen-8-one;-   (9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-5,9-dimethyl-4,5,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),3,14,16-pentaen-8-one;-   (9R,13S)-13-[4-(1-benzyl-5-chloro-1H-indazol-7-yl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one;-   (9R,13S)-13-{4-[5-chloro-2-(1H-1,2,3-triazol-1-yl)phenyl]-5-methyl-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one;-   (9R,13S)-13-{4-[5-chloro-2-(1-methyl-1H-pyrazol-3-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one;-   (9R,13S)-13-{4-[5-chloro-2-(1H-imidazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one;-   (9R,13S)-13-[4-(5-chloro-1H-indazol-7-yl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one;-   (9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-4-(6-methoxypyridin-3-yl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2,5,14,16-pentaen-8-one;-   (10R,14S)-3-chloro-14-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-10-methyl-5,8-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-9-one;-   (9R,13S)-13-{4-[5-chloro-2-(1H-pyrazol-4-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one;-   N-benzyl-4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}benzamide;-   (9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-4-(pyridin-2-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2,5,14,16-pentaen-8-one;-   1-(4-chloro-3-fluoro-2-{1-[(9R,13S)-3-(²H₃)methyl-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)-1H-pyrazole-4-carbonitrile;-   1-(4-chloro-2-{1-[(9R,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}-3-fluorophenyl)-1H-pyrazole-4-carbonitrile;-   (9R,13S)-13-{4-[5-chloro-2-(1-propyl-1H-pyrazol-4-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one;-   (9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-4-(pyridin-4-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2,5,14,16-pentaen-8-one;-   (9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-3-(pyridin-4-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one;-   1-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)-1H-imidazole-4-carbonitrile;-   N-(4-chloro-2-{1-[(9R,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)-2,2,2-trifluoroacetamide;-   (9R,13S)-13-(4-{5-chloro-2-[1-(propan-2-yl)-1H-pyrazol-4-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one;-   (9R,13S)-13-{4-[5-(difluoromethoxy)-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one;-   (9R,13S)-3-(difluoromethyl)-13-(4-{5-methoxy-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one;-   (9R,13S)-13-(4-{5-chloro-2-[1-(2-methylpropyl)-1H-pyrazol-4-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one;-   (9R,13S)-13-{4-[2-(1-benzyl-1H-pyrazol-4-yl)-5-chlorophenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one;-   (9R,13S)-13-{4-[5-chloro-2-(1-methyl-1H-1,2,3-triazol-4-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one;-   (10R,14S)-14-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-4-fluoro-10-methyl-5,8,16-triazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-9-one;-   (9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-4-(6-methoxypyridin-2-yl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2,5,14,16-pentaen-8-one;-   (9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-4-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2,5,14,16-pentaen-8-one;-   (9R,13S)-13-{4-[5-chloro-2-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one;-   (9R,13S)-13-(4-{5-chloro-2-[1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one;-   3-[(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2,5,14,16-pentaen-4-yl]benzonitrile;-   (9R,13S)-13-{4-[5-chloro-2-(5-methyl-1H-imidazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one    trifluoroacetate;-   (9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-4-(1H-pyrazol-3-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2,5,14,16-pentaen-8-one;-   (9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-4-(pyrimidin-5-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2,5,14,16-pentaen-8-one;-   (9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-9-methyl-4-(pyrazin-2-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2,5,14,16-pentaen-8-one;-   (9R,13S)-13-[4-(2-Amino-5-chlorophenyl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one;-   (9R,13S)-13-(4-{3-chloro-6-[1-(difluoromethyl)-1H-pyrazol-4-yl]-2-fluorophenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one;-   (9R,13S)-13-[4-(5-chloro-1H-indol-7-yl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one;-   (9R,13S)-13-[4-(6-chloro-1H-indazol-4-yl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one;-   (14S)-14-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-10-methyl-5,8,16-triazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-9-one    trifluoroacetate;-   (9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-9-methyl-4-(6-oxo-1,6-dihydropyridazin-4-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2,5,14,16-pentaen-8-one;-   (9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-4-(6-methoxypyrazin-2-yl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2,5,14,16-pentaen-8-one;-   (9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-4-(5-fluoro-2-methoxypyridin-4-yl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2,5,14,16-pentaen-8-one;-   (9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaene-17-carbonitrile;-   (9R,13S)-13-{4-[5-chloro-2-(4-methyl-1H-imidazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one;-   (9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-4-(5-fluoro-2-hydroxypyridin-4-yl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2,5,14,16-pentaen-8-one;-   (9R,13S)-13-{4-[5-chloro-2-(1,3-oxazol-2-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one;-   (9R,13S)-13-(4-{5-chloro-2-[(pyrazin-2-yl)amino]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one;-   (9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-4-(4-hydroxypyrimidin-5-yl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2,5,14,16-pentaen-8-one;-   ethyl    1-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)-3-methyl-1H-pyrazole-4-carboxylate;-   (9R,13S)-13-{4-[5-chloro-2-(3,4-dimethyl-1H-pyrazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one;-   ethyl    1-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)-1H-pyrazole-4-carboxylate;-   (9R,13S)-13-[4-(5-chloro-2-hydroxyphenyl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one;-   (9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-imidazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one;-   (9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-4-methanesulfonyl-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2,5,14,16-pentaen-8-one;-   (9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-methanesulfonyl-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one;-   (9R,13S)-13-(4-{2,3-difluoro-6-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one;-   methyl    1-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)-1H-imidazole-4-carboxylate;-   (9R,13S)-13-[4-(2,5-dichlorophenyl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one;-   (9R,13R)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,18-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one    trifluoroacetate;-   (9R,13S)-13-(4-{2,3-difluoro-6-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(²H₃)methyl-9-methyl-3,4,7,17-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one;-   1-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)-1H-imidazole-4-carboxylic    acid;-   (9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,18-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one;-   (10R,14S)-14-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-10-methyl-3,5,8-triazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-9-one;-   (9R,13S)-13-{4-[5-chloro-1-(2-hydroxyethyl)-1H-indazol-7-yl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one;-   (9R,13S)-13-[4-(5-chloro-1-methyl-1H-indol-7-yl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one;-   (9R,13S)-13-{4-[5-chloro-2-(2-hydroxyethyl)-2H-indazol-7-yl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one;-   (9R,13S)-13-[4-(6-chloro-1-methyl-1H-indazol-4-yl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one;-   (9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-4-(6-hydroxypyridin-3-yl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2,5,14,16-pentaen-8-one;-   (9R,13S)-13-{4-[5-chloro-2-(1,2,3-thiadiazol-4-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one;-   (9R,13S)-13-(4-{3-chloro-2-fluoro-6-[4-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one;-   (9R,13S)-13-[4-(3-chloro-2,6-difluorophenyl)-6-oxo-1,6-dihydropyrimidin-1-yl]-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one;-   (9R,13S)-13-{4-[5-chloro-2-(1,2,3-thiadiazol-4-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one;-   (9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-4-(2-hydroxypyridin-4-yl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2,5,14,16-pentaen-8-one;-   (9R,13S)-13-[4-(3-chloro-2,6-difluorophenyl)-6-oxo-1,6-dihydropyrimidin-1-yl]-9-methyl-4-(pyrimidin-5-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2,5,14,16-pentaen-8-one;-   (9R,13S)-13-{4-[5-chloro-2-(pyridazin-4-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one;-   (9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-4-(2-hydroxypyrimidin-5-yl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2,5,14,16-pentaen-8-one;-   (10R,14S)-14-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-10-methyl-5,8,17-triazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-9-one;-   (9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-4-(piperidin-4-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2,5,14,16-pentaen-8-one;-   1-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}-3-fluorophenyl)-1H-pyrazole-4-carbonitrile;-   (9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-4-(1H-imidazol-4-yl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2,5,14,16-pentaen-8-one;-   (9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-4-(1H-1,2,4-triazol-5-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2,5,14,16-pentaen-8-one;-   N-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)-2,2,2-trifluoroacetamide;-   (9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-4-(2-hydroxypyridin-3-yl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2,5,14,16-pentaen-8-one;-   (9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-3-(1H-pyrazol-3-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one;-   (9R,13S)-13-[4-(2-amino-5-chlorophenyl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one;-   (9R,13S)-13-(4-{5-chloro-2-[(pyrimidin-4-yl)amino]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one;-   (9R,13S)-13-{4-[2-(aminomethyl)-5-chlorophenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one;-   (9R,13S)-13-{4-[5-chloro-2-(pyridin-2-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one;-   (9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-4-(2-methoxypyridin-3-yl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2,5,14,16-pentaen-8-one;-   (9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(6-methoxypyrimidin-4-yl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one;-   (9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-4-(6-methoxypyrimidin-4-yl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2,5,14,16-pentaen-8-one;-   (9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-4-(6-hydroxypyrimidin-4-yl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2,5,14,16-pentaen-8-one;-   (9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-4-(2-methoxypyridin-4-yl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2,5,14,16-pentaen-8-one;-   (9R,13S)-13-{4-[5-chloro-2-(4-methylphenyl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one;-   (9R,13S)-13-{4-[5-chloro-2-(3-chlorophenyl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one;-   (9R,13S)-13-{4-[5-chloro-2-(3-methoxyphenyl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one;-   (9R,13S)-13-{4-[5-chloro-2-(2-methylphenyl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one;-   (9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethoxy)phenyl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one;-   (9R,13S)-13-{4-[5-chloro-2-(2-chlorophenyl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one;-   (9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)phenyl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one;-   (9R,13S)-13-(4-{5-chloro-2-[4-(propan-2-ylsulfanyl)phenyl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one;-   4-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)benzene-1-sulfonamide;-   (9R,13S)-13-(4-{5-chloro-2-[4-(difluoromethoxy)phenyl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one;-   N-[3-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)phenyl]methanesulfonamide;-   3-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)benzonitrile;-   (9R,13S)-13-(4-{5-chloro-2-[3-(trifluoromethoxy)phenyl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one;-   (9R,13S)-13-{4-[5-chloro-2-(3-methanesulfonylphenyl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one;-   methyl    4-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)benzoate;-   (9R,13S)-13-{4-[5-chloro-2-(3-methylphenyl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one;-   4-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)benzonitrile;-   (9R,13S)-13-{4-[5-chloro-2-(1-methyl-1H-indol-5-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one;-   (9R,13S)-13-{4-[5-chloro-2-(isoquinolin-5-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one;-   methyl    3-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)benzoate;-   N-[4-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)phenyl]methanesulfonamide;-   (9R,13S)-13-(4-{5-chloro-2-[3-(trifluoromethyl)phenyl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one;-   (9R,13S)-13-{4-[5-chloro-2-(4-methoxyphenyl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one;-   (9R,13S)-13-{4-[5-chloro-2-(4-chlorophenyl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one;-   (9R,13S)-13-{4-[5-chloro-2-(pyridin-4-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one;-   (9R,13S)-13-{4-[5-chloro-2-(isoquinolin-7-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one;-   (9R,13S)-13-{4-[5-chloro-2-(pyrimidin-5-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one;-   ethyl    2-[4-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)-1H-pyrazol-1-yl]acetate;-   (9R,13S)-13-{4-[5-chloro-2-(1-ethyl-1H-pyrazol-4-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one;    and-   (9R,13S)-13-(4-{5-chloro-2-[1-(4-fluorophenyl)-1H-pyrazol-4-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one.

In another embodiment, the compounds of the present invention haveFactor XIa or plasma kallikrein Ki values≤10 μM.

In another embodiment, the compounds of the present invention haveFactor XIa or plasma kallikrein Ki values≤1 μM.

In another embodiment, the compounds of the present invention haveFactor XIa or plasma kallikrein Ki values≤0.5 μM.

In another embodiment, the compounds of the present invention haveFactor XIa or plasma kallikrein Ki values≤0.1 μM.

II. Other Embodiments of the Invention

In another embodiment, the present invention provides a compositioncomprising at least one of the compounds of the present invention or astereoisomer, a tautomer, a pharmaceutically acceptable salt, or asolvate thereof.

In another embodiment, the present invention provides a pharmaceuticalcomposition comprising a pharmaceutically acceptable carrier and atleast one of the compounds of the present invention or a stereoisomer, atautomer, a pharmaceutically acceptable salt, or a solvate, thereof.

In another embodiment, the present invention provides a pharmaceuticalcomposition, comprising: a pharmaceutically acceptable carrier and atherapeutically effective amount of at least one of the compounds of thepresent invention or a stereoisomer, a tautomer, a pharmaceuticallyacceptable salt, or a solvate thereof.

In another embodiment, the present invention provides a process formaking a compound of the present invention.

In another embodiment, the present invention provides an intermediatefor making a compound of the present invention.

In another embodiment, the present invention provides a pharmaceuticalcomposition further comprising additional therapeutic agent(s). In apreferred embodiment, the present invention provides pharmaceuticalcomposition, wherein the additional therapeutic agent(s) are ananti-platelet agent or a combination thereof. Preferably, theanti-platelet agent(s) are clopidogrel and/or aspirin, or a combinationthereof.

In another embodiment, the present invention provides a method for thetreatment and/or prophylaxis of a thromboembolic disorder comprisingadministering to a patient in need of such treatment and/or prophylaxisa therapeutically effective amount of at least one of the compounds ofthe present invention or a stereoisomer, a tautomer, a pharmaceuticallyacceptable salt, or a solvate thereof.

In another embodiment, the present invention provides a compound of thepresent invention or a stereoisomer, a tautomer, a pharmaceuticallyacceptable salt, or a solvate thereof, for use in therapy.

In another embodiment, the present invention provides a compound of thepresent invention or a stereoisomer, a tautomer, a pharmaceuticallyacceptable salt, or a solvate thereof, for use in therapy for thetreatment and/or prophylaxis of a thromboembolic disorder.

In another embodiment, the present invention also provides the use of acompound of the present invention or a stereoisomer, a tautomer, apharmaceutically acceptable salt, or a solvate thereof, for themanufacture of a medicament for the treatment and/or prophylaxis of athromboembolic disorder.

In another embodiment, the present invention provides a method fortreatment and/or prophylaxis of a thromboembolic disorder, comprising:administering to a patient in need thereof a therapeutically effectiveamount of a first and second therapeutic agent, wherein the firsttherapeutic agent is a compound of the present invention or astereoisomer, a tautomer, a pharmaceutically acceptable salt, or asolvate thereof, and the second therapeutic agent is at least one agentselected from a factor Xa inhibitor such as apixaban, rivaroxaban,betrixaban, edoxaban, an anti-coagulant agent, an anti-platelet agent, athrombin inhibiting agent such as dabigatran, a thrombolytic agent, anda fibrinolytic agent. Preferably, the second therapeutic agent is atleast one agent selected from warfarin, unfractionated heparin, lowmolecular weight heparin, synthetic pentasaccharide, hirudin,argatroban, aspirin, ibuprofen, naproxen, sulindac, indomethacin,mefenamate, droxicam, diclofenac, eribaxaban, sulfinpyrazone, piroxicam,ticlopidine, clopidogrel, tirofiban, eptifibatide, abciximab,melagatran, desulfatohirudin, tissue plasminogen activator, modifiedtissue plasminogen activator, anistreplase, urokinase, andstreptokinase. Preferably, the second therapeutic agent is at least oneanti-platelet agent. Preferably, the anti-platelet agent(s) areclopidogrel and/or aspirin, or a combination thereof.

The thromboembolic disorder includes arterial cardiovascularthromboembolic disorders, venous cardiovascular thromboembolicdisorders, arterial cerebrovascular thromboembolic disorders, and venouscerebrovascular thromboembolic disorders. Examples of the thromboembolicdisorder include, but are not limited to, unstable angina, an acutecoronary syndrome, atrial fibrillation, first myocardial infarction,recurrent myocardial infarction, ischemic sudden death, transientischemic attack, stroke, atherosclerosis, peripheral occlusive arterialdisease, venous thrombosis, deep vein thrombosis, thrombophlebitis,arterial embolism, coronary arterial thrombosis, cerebral arterialthrombosis, cerebral embolism, kidney embolism, pulmonary embolism, andthrombosis resulting from medical implants, devices, or procedures inwhich blood is exposed to an artificial surface that promotesthrombosis.

In another embodiment, the present invention provides a method for thetreatment and/or prophylaxis of an inflammatory disorder comprising:administering to a patient in need of such treatment and/or prophylaxisa therapeutically effective amount of at least one of the compounds ofthe present invention or a stereoisomer, a tautomer, a pharmaceuticallyacceptable salt, or a solvate thereof. Examples of the inflammatorydisorder include, but are not limited to, sepsis, acute respiratorydistress syndrome, and systemic inflammatory response syndrome.

In another embodiment, the present invention provides a method for theprophylaxis of a disease or condition in which plasma kallikreinactivity is implicated comprising administering to a patient in need ofsuch treatment and/or prophylaxis a therapeutically effective amount ofat least one of the compounds of the present invention or astereoisomer, a tautomer, a pharmaceutically acceptable salt, or asolvate thereof.

The disease or condition in which plasma kallikrein activity isimplicated includes, but not limited to, impaired visual acuity,diabetic retinopathy, diabetic macular edema, hereditary angioedema,diabetes, pancreatitis, nephropathy, cardio myopathy, neuropathy,inflammatory bowel disease, arthritis, inflammation, septic shock,hypotension, cancer, adult respiratory distress syndrome, disseminatedintravascular coagulation, and cardiopulmonary bypass surgery.

In another embodiment, the present invention provides a combinedpreparation of a compound of the present invention and additionaltherapeutic agent(s) for simultaneous, separate or sequential use intherapy.

In another embodiment, the present invention provides a combinedpreparation of a compound of the present invention and additionaltherapeutic agent(s) for simultaneous, separate or sequential use intreatment and/or prophylaxis of a thromboembolic disorder.

The present invention may be embodied in other specific forms withoutdeparting from the spirit or essential attributes thereof. Thisinvention encompasses all combinations of preferred aspects of theinvention noted herein. It is understood that any and all embodiments ofthe present invention may be taken in conjunction with any otherembodiment or embodiments to describe additional embodiments. It is alsoto be understood that each individual element of the embodiments is itsown independent embodiment. Furthermore, any element of an embodiment ismeant to be combined with any and all other elements from any embodimentto describe an additional embodiment.

III. Chemistry

Throughout the specification and the appended claims, a given chemicalformula or name shall encompass all stereo and optical isomers andracemates thereof where such isomers exist. Unless otherwise indicated,all chiral (enantiomeric and diastereomeric) and racemic forms arewithin the scope of the invention. Many geometric isomers of C═C doublebonds, C═N double bonds, ring systems, and the like can also be presentin the compounds, and all such stable isomers are contemplated in thepresent invention. Cis- and trans-(or E- and Z-) geometric isomers ofthe compounds of the present invention are described and may be isolatedas a mixture of isomers or as separated isomeric forms. The presentcompounds can be isolated in optically active or racemic forms.Optically active forms may be prepared by resolution of racemic forms orby synthesis from optically active starting materials. All processesused to prepare compounds of the present invention and intermediatesmade therein are considered to be part of the present invention. Whenenantiomeric or diastereomeric products are prepared, they may beseparated by conventional methods, for example, by chromatography orfractional crystallization. Depending on the process conditions the endproducts of the present invention are obtained either in free (neutral)or salt form. Both the free form and the salts of these end products arewithin the scope of the invention. If so desired, one form of a compoundmay be converted into another form. A free base or acid may be convertedinto a salt; a salt may be converted into the free compound or anothersalt; a mixture of isomeric compounds of the present invention may beseparated into the individual isomers. Compounds of the presentinvention, free form and salts thereof, may exist in multiple tautomericforms, in which hydrogen atoms are transposed to other parts of themolecules and the chemical bonds between the atoms of the molecules areconsequently rearranged. It should be understood that all tautomericforms, insofar as they may exist, are included within the invention.

The term “stereoisomer” refers to isomers of identical constitution thatdiffer in the arrangement of their atoms in space. Enantiomers anddiastereomers are examples of stereoisomers. The term “enantiomer”refers to one of a pair of molecular species that are mirror images ofeach other and are not superimposable. The term “diastereomer” refers tostereoisomers that are not mirror images. The term “racemate” or“racemic mixture” refers to a composition composed of equimolarquantities of two enantiomeric species, wherein the composition isdevoid of optical activity.

The symbols “R” and “S” represent the configuration of substituentsaround a chiral carbon atom(s). The isomeric descriptors “R” and “S” areused as described herein for indicating atom configuration(s) relativeto a core molecule and are intended to be used as defined in theliterature (IUPAC Recommendations 1996, Pure and Applied Chemistry,68:2193-2222 (1996)).

The term “chiral” refers to the structural characteristic of a moleculethat makes it impossible to superimpose it on its mirror image. The term“homochiral” refers to a state of enantiomeric purity. The term “opticalactivity” refers to the degree to which a homochiral molecule ornonracemic mixture of chiral molecules rotates a plane of polarizedlight.

As used herein, the term “alkyl” or “alkylene” is intended to includeboth branched and straight-chain saturated aliphatic hydrocarbon groupshaving the specified number of carbon atoms. For example, “C₁ to C₁₀alkyl” or “C₁₋₁₀ alkyl” (or alkylene), is intended to include C₁, C₂,C₃, C₄, C₅, C₆, C₇, C₈, C₉, and C₁₀ alkyl groups. Additionally, forexample, “C₁ to C₆ alkyl” or “C₁-C₆ alkyl” denotes alkyl having 1 to 6carbon atoms. Alkyl group can be unsubstituted or substituted with atleast one hydrogen being replaced by another chemical group. Examplealkyl groups include, but are not limited to, methyl (Me), ethyl (Et),propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl,t-butyl), and pentyl (e.g., n-pentyl, isopentyl, neopentyl). When “C₀alkyl” or “C₀ alkylene” is used, it is intended to denote a direct bond.“Alkyl” also includes deuteroalkyl such as CD₃.

“Alkenyl” or “alkenylene” is intended to include hydrocarbon chains ofeither straight or branched configuration having one or more, preferablyone to three, carbon-carbon double bonds that may occur in any stablepoint along the chain. For example, “C₂ to C₆ alkenyl” or “C₂₋₆ alkenyl”(or alkenylene), is intended to include C₂, C₃, C₄, C₅, and C₆ alkenylgroups; such as ethenyl, propenyl, butenyl, pentenyl, and hexenyl.

“Alkynyl” or “alkynylene” is intended to include hydrocarbon chains ofeither straight or branched configuration having one or more, preferablyone to three, carbon-carbon triple bonds that may occur in any stablepoint along the chain. For example, “C₂ to C₆ alkynyl” or “C₂₋₆ alkynyl”(or alkynylene), is intended to include C₂, C₃, C₄, C₅, and C₆ alkynylgroups; such as ethynyl, propynyl, butynyl, pentynyl, and hexynyl.

The term “alkoxy” or “alkyloxy” refers to an —O-alkyl group. “C₁ to C₆alkoxy” or “C₁₋₆ alkoxy” (or alkyloxy), is intended to include C₁, C₂,C₃, C₄, C₅, and C₆ alkoxy groups. Example alkoxy groups include, but arenot limited to, methoxy, ethoxy, propoxy (e.g., n-propoxy andisopropoxy), and t-butoxy. Alkoxy also includes deuteroalkoxy such asOCD₃. Similarly, “alkylthio” or “thioalkoxy” represents an alkyl groupas defined above with the indicated number of carbon atoms attachedthrough a sulphur bridge; for example methyl-S- and ethyl-S-.

“Halo” or “halogen” includes fluoro, chloro, bromo, and iodo.“Haloalkyl” is intended to include both branched and straight-chainsaturated aliphatic hydrocarbon groups having the specified number ofcarbon atoms, substituted with 1 or more halogens. Examples of haloalkylinclude, but are not limited to, fluoromethyl, difluoromethyl,trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl,2,2,2-trifluoroethyl, heptafluoropropyl, and heptachloropropyl. Examplesof haloalkyl also include “fluoroalkyl” that is intended to include bothbranched and straight-chain saturated aliphatic hydrocarbon groupshaving the specified number of carbon atoms, substituted with 1 or morefluorine atoms.

“Haloalkoxy” or “haloalkyloxy” represents a haloalkyl group as definedabove with the indicated number of carbon atoms attached through anoxygen bridge. For example, “C₁ to C₆ haloalkoxy” or “C₁₋₆ haloalkoxy”,is intended to include C₁, C₂, C₃, C₄, C₅, and C₆ haloalkoxy groups.Examples of haloalkoxy include, but are not limited to,trifluoromethoxy, 2,2,2-trifluoroethoxy, and pentafluorothoxy.Similarly, “haloalkylthio” or “thiohaloalkoxy” represents a haloalkylgroup as defined above with the indicated number of carbon atomsattached through a sulphur bridge; for example trifluoromethyl-S-, andpentafluoroethyl-S-.

The term “amino”, as used herein, refers to —NH₂.

The term “substituted amino”, as used herein, refers to the definedterms below having the suffix “amino” such as “arylamino”, “alkylamino”,“arylamino”, etc.

The term “alkoxycarbonyl”, as used herein, refers to an alkoxy groupattached to the parent molecular moiety through a carbonyl group.

The term “alkoxycarbonylamino”, as used herein, refers to an —NHRwherein R is an alkoxycarbonyl group.

The term “alkylamino”, as used herein refers to —NHR, wherein R is analkyl group.

The term “alkylcarbonyl”, as used herein, refers to an alkyl groupattached to the parent molecular moiety through a carbonyl group.

The term “alkylcarbonylamino”, as used herein, refers to —NHR wherein Ris an alkylcarbonyl group.

The term “aminosulfonyl”, as used herein, refers to —SO₂NH₂.

The term “arylalkyl”, as used herein, refers to an alkyl groupsubstituted with one, two, or three aryl groups.

The term “arylamino”, as used herein, refers to —NHR wherein R is anaryl group.

The term “arylcarbonyl”, as used herein, refers to an aryl groupattached to the parent molecular moiety through a carbonyl group.

The term “arylcarbonylamino”, as used herein refers to —NHR wherein R isan arylcarbonyl group.

The term “cyano”, as used herein, refers to —CN.

The term “cycloalkylamino”, as used herein, refers to —NHR wherein R isa cycloalkyl group.

The term “cycloalkylcarbonyl”, as used herein, refers to a cycloalkylgroup attached to the parent molecular moiety through a carbonyl group.

The term “cycloalkylcarbonylamino”, as used herein, refers to —NHRwherein R is a cycloalkylcarbonyl group.

The term “cycloalkyloxy”, as used herein, refers to a cycloalkyl groupattached to the parent molecular moiety through an oxygen atom.

The term “dialkylamino”, as used herein, refers to NR₂, wherein each Ris an alkyl group. The two alkyl groups are the same or different.

The term “haloalkoxy”, as used herein, refers to a haloalkyl groupattached to the parent molecular moiety through an oxygen atom.

The term “haloalkyl”, as used herein, refers to an alkyl groupsubstituted by one, two, three, or four halogen atoms.

The term “haloalkylamino”, as used herein, refers to —NHR wherein R is ahaloalkyl group.

The term “carbonyl” refers to C(═O) or C(O).

The term “carboxyl” or “carboxyl” refers to C(═O)OH.

The terms “carboxyl ester” and “oxycarbonyl” refer to the groups—C(O)O-alkyl, —C(O)O-substituted alkyl, —C(O)O-alkenyl,—C(O)O-substituted alkenyl, —C(O)O-alkynyl, C(O)O-substituted alkynyl,—C(O)O-cycloalkyl, —C(O)O-substituted cycloalkyl, —C(O)O-aryl,—C(O)O-substituted aryl, —C(O)O-heteroaryl, —C(O)O-substitutedheteroaryl, —C(O)O-heterocyclic, and —C(O)O-substituted heterocyclic.

The term “aminoacyl” or “amide”, or the prefix “carbamoyl”,“carboxamide”, “substituted carbamoyl” or “substituted carboxamide”refers to the group —C(O)NRR where each R is independently selected fromthe group consisting of hydrogen, alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, aryl, substitutedaryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substitutedheteroaryl, heterocyclic, and substituted heterocyclic.

The term “haloalkylcarbonyl”, as used herein, refers to a haloalkylgroup attached to the parent molecular moiety through a carbonyl group.

The term “haloalkylcarbonylamino”, as used herein, refers to —NHRwherein R is a haloalkylcarbonyl group.

The terms “alkylcarbonyl” refer to an alkyl or substituted alkyl bondedto a carbonyl.

The term “alkoxycarbonyl”, as used herein, refers to an alkoxy groupattached to the parent molecular moiety through a carbonyl group.

The term “hydroxy” or “hydroxyl” refers to OH.

As used herein the term “thiol” means —SH. A thiol may be substitutedwith a substituent disclosed herein, in particular alkyl(thioalkyl),aryl(thioaryl), or alkoxy(thioalkoxy).

As used herein the term “sulfonyl”, used alone or linked to other termssuch as alkylsulfonyl or arylsulfonyl, refers to the divalent radicals—SO₂—. In aspects of the invention a sulfonyl group, the sulfonyl groupmay be attached to a substituted or unsubstituted hydroxyl, alkyl group,ether group, alkenyl group, alkynyl group, aryl group, cycloalkyl group,cycloalkenyl group, cycloalkynyl group, heterocyclic group,carbohydrate, peptide, or peptide derivative.

The term “cycloalkyl” refers to cyclized alkyl groups, including mono-,bi- or poly-cyclic ring systems. “C₃ to C₇ cycloalkyl” or “C₃₋₇cycloalkyl” is intended to include C₃, C₄, C₅, C₆, and C₇ cycloalkylgroups. Example cycloalkyl groups include, but are not limited to,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and norbomyl. Branchedcycloalkyl groups such as 1-methylcyclopropyl and 2-methylcyclopropylare included in the definition of “cycloalkyl”.

As used herein, “carbocycle”, “carbocyclyl”, or “carbocyclic residue” isintended to mean any stable 3-, 4-, 5-, 6-, 7-, or 8-membered monocyclicor bicyclic or 7-, 8-, 9-, 10-, 11-, 12-, or 13-membered bicyclic ortricyclic hydrocarbon ring, any of which may be saturated, partiallyunsaturated, unsaturated or aromatic. Examples of such carbocyclylsinclude, but are not limited to, cyclopropyl, cyclobutyl, cyclobutenyl,cyclopentyl, cyclopentenyl, cyclohexyl, cycloheptenyl, cycloheptyl,cycloheptenyl, adamantyl, cyclooctyl, cyclooctenyl, cyclooctadienyl,[3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane(decalin), [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl,adamantyl, anthracenyl, and tetrahydronaphthyl (tetralin). As shownabove, bridged rings are also included in the definition of carbocyclyl(e.g., [2.2.2]bicyclooctane). Preferred carbocyclyls, unless otherwisespecified, are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl,and indanyl. When the term “carbocyclyl” is used, it is intended toinclude “aryl”. A bridged ring occurs when one or more carbon atoms linktwo non-adjacent carbon atoms. Preferred bridges are one or two carbonatoms. It is noted that a bridge always converts a monocyclic ring intoa tricyclic ring. When a ring is bridged, the substituents recited forthe ring may also be present on the bridge.

As used herein, the term “bicyclic carbocyclyl” or “bicyclic carbocyclicgroup” is intended to mean a stable 9- or 10-membered carbocyclic ringsystem that contains two fused rings and consists of carbon atoms. Ofthe two fused rings, one ring is a benzo ring fused to a second ring;and the second ring is a 5- or 6-membered carbon ring which issaturated, partially unsaturated, or unsaturated. The bicycliccarbocyclic group may be attached to its pendant group at any carbonatom which results in a stable structure. The bicyclic carbocyclic groupdescribed herein may be substituted on any carbon if the resultingcompound is stable. Examples of a bicyclic carbocyclic group are, butnot limited to, naphthyl, 1,2-dihydronaphthyl,1,2,3,4-tetrahydronaphthyl, and indanyl.

“Aryl” groups refer to monocyclic or polycyclic aromatic hydrocarbons,including, for example, phenyl, naphthyl, and phenanthranyl. Arylmoieties are well known and described, for example, in Lewis, R. J.,ed., Hawley's Condensed Chemical Dictionary, 13th Edition, John Wiley &Sons, Inc., New York (1997).

“C₆ or C₁₀ aryl” or “C₆₋₁₀ aryl” refers to phenyl and naphthyl. Unlessotherwise specified, “aryl”, “C₆ or C₁₀ aryl” or “C₆₋₁₀ aryl” or“aromatic residue” may be unsubstituted or substituted with 1 to 5groups, preferably 1 to 3 groups, OH, OCH₃, Cl, F, Br, I, CN, NO₂, NH₂,N(CH₃)H, N(CH₃)₂, CF₃, OCF₃, C(═O)CH₃, SCH₃, S(═O)CH₃, S(═O)₂CH₃, CH₃,CH₂CH₃, CO₂H, and CO₂CH₃.

The term “benzyl”, as used herein, refers to a methyl group on which oneof the hydrogen atoms is replaced by a phenyl group, wherein said phenylgroup may optionally be substituted with 1 to 5 groups, preferably 1 to3 groups, OH, OCH₃, Cl, F, Br, I, CN, NO₂, NH₂, N(CH₃)H, N(CH₃)₂, CF₃,OCF₃, C(═O)CH₃, SCH₃, S(═O)CH₃, S(═O)₂CH₃, CH₃, CH₂CH₃, CO₂H, andCO₂CH₃.

As used herein, the term “heterocycle”, “heterocyclyl” or “heterocyclicring” is intended to mean a stable 3-, 4-, 5-, 6-, or 7-memberedmonocyclic or bicyclic or 7-, 8-, 9-, 10-, 11-, 12-, 13-, or 14-memberedpolycyclic heterocyclic ring that is saturated, partially unsaturated,or fully unsaturated, and that contains carbon atoms and 1, 2, 3 or 4heteroatoms independently selected from the group consisting of N, O andS; and including any polycyclic group in which any of the above-definedheterocyclic rings is fused to a benzene ring. The nitrogen and sulfurheteroatoms may optionally be oxidized (i.e., N→O and S(O)_(p), whereinp is 0, 1 or 2). The nitrogen atom may be substituted or unsubstituted(i.e., N or NR wherein R is H or another substituent, if defined). Theheterocyclic ring may be attached to its pendant group at any heteroatomor carbon atom that results in a stable structure. The heterocyclicrings described herein may be substituted on carbon or on a nitrogenatom if the resulting compound is stable. A nitrogen in the heterocyclylmay optionally be quaternized. It is preferred that when the totalnumber of S and O atoms in the heterocyclyl exceeds 1, then theseheteroatoms are not adjacent to one another. It is preferred that thetotal number of S and O atoms in the heterocyclyl is not more than 1.When the term “heterocyclyl” is used, it is intended to includeheteroaryl.

Examples of heterocyclyls include, but are not limited to, acridinyl,azetidinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl,benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl,benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl,benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl,chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl,imidazolinyl, imidazolyl, 1H-indazolyl, imidazolopyridinyl, indolenyl,indolinyl, indolizinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl,isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl,isothiazolyl, isothiazolopyridinyl, isoxazolyl, isoxazolopyridinyl,methylenedioxyphenyl, morpholinyl, naphthyridinyl,octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl,oxazolyl, oxazolopyridinyl, oxazolidinylperimidinyl, oxindolyl,pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl,phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl,piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl,pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolopyridinyl,pyrazolyl, pyridazinyl, pyridooxazolyl, pyridoimidazolyl,pyridothiazolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl,2-pyrrolidonyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl,4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrazolyl,tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl,6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl,thienyl, thiazolopyridinyl, thienothiazolyl, thienooxazolyl,thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl,1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl. Alsoincluded are fused ring and spiro compounds containing, for example, theabove heterocyclyls.

Examples of 5- to 10-membered heterocyclyls include, but are not limitedto, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrazinyl,piperazinyl, piperidinyl, imidazolyl, imidazolidinyl, indolyl,tetrazolyl, isoxazolyl, morpholinyl, oxazolyl, oxadiazolyl,oxazolidinyl, tetrahydrofuranyl, thiadiazinyl, thiadiazolyl, thiazolyl,triazinyl, triazolyl, benzimidazolyl, 1H-indazolyl, benzofuranyl,benzothiofuranyl, benztetrazolyl, benzotriazolyl, benzisoxazolyl,benzoxazolyl, oxindolyl, benzoxazolinyl, benzthiazolyl,benzisothiazolyl, isatinoyl, isoquinolinyl, octahydroisoquinolinyl,tetrahydroisoquinolinyl, tetrahydroquinolinyl, isoxazolopyridinyl,quinazolinyl, quinolinyl, isothiazolopyridinyl, thiazolopyridinyl,oxazolopyridinyl, imidazolopyridinyl, and pyrazolopyridinyl.

Examples of 5- to 6-membered heterocyclyls include, but are not limitedto, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrazinyl,piperazinyl, piperidinyl, imidazolyl, imidazolidinyl, indolyl,tetrazolyl, isoxazolyl, morpholinyl, oxazolyl, oxadiazolyl,oxazolidinyl, tetrahydrofuranyl, thiadiazinyl, thiadiazolyl, thiazolyl,triazinyl, and triazolyl. Also included are fused ring and spirocompounds containing, for example, the above heterocyclyls.

As used herein, the term “bicyclic heterocyclyl” “bicyclic heterocyclyl”or “bicyclic heterocyclic group” is intended to mean a stable 9- or10-membered heterocyclic ring system which contains two fused rings andconsists of carbon atoms and 1, 2, 3, or 4 heteroatoms independentlyselected from the group consisting of N, O and S. Of the two fusedrings, one ring is a 5- or 6-membered monocyclic aromatic ringcomprising a 5-membered heteroaryl ring, a 6-membered heteroaryl ring ora benzo ring, each fused to a second ring. The second ring is a 5- or6-membered monocyclic ring which is saturated, partially unsaturated, orunsaturated, and comprises a 5-membered heterocyclyl, a 6-memberedheterocyclyl or a carbocyclyl (provided the first ring is not benzo whenthe second ring is a carbocyclyl).

The bicyclic heterocyclic group may be attached to its pendant group atany heteroatom or carbon atom which results in a stable structure. Thebicyclic heterocyclic group described herein may be substituted oncarbon or on a nitrogen atom if the resulting compound is stable. It ispreferred that when the total number of S and O atoms in theheterocyclyl exceeds 1, then these heteroatoms are not adjacent to oneanother. It is preferred that the total number of S and O atoms in theheterocyclyl is not more than 1.

Examples of a bicyclic heterocyclic group are, but not limited to,quinolinyl, isoquinolinyl, phthalazinyl, quinazolinyl, indolyl,isoindolyl, indolinyl, 1H-indazolyl, benzimidazolyl,1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl,5,6,7,8-tetrahydroquinolinyl, 2,3-dihydrobenzofuranyl, chromanyl,1,2,3,4-tetrahydroquinoxalinyl, and 1,2,3,4-tetrahydroquinazolinyl.

As used herein, the term “aromatic heterocyclic group” or “heteroaryl”is intended to mean stable monocyclic and polycyclic aromatichydrocarbons that include at least one heteroatom ring member such assulfur, oxygen, or nitrogen. Heteroaryl groups include, withoutlimitation, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl,furyl, quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl,pyrroyl, oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl,pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl,isothiazolyl, purinyl, carbazolyl, benzimidazolyl, indolinyl,benzodioxolanyl, and benzodioxane. Heteroaryl groups are substituted orunsubstituted. The nitrogen atom is substituted or unsubstituted (i.e.,N or NR wherein R is H or another substituent, if defined). The nitrogenand sulfur heteroatoms may optionally be oxidized (i.e., N→O andS(O)_(p), wherein p is 0, 1 or 2).

Bridged rings are also included in the definition of heterocyclyl. Abridged ring occurs when one or more atoms (i.e., C, O, N, or S) linktwo non-adjacent carbon or nitrogen atoms. Examples of bridged ringsinclude, but are not limited to, one carbon atom, two carbon atoms, onenitrogen atom, two nitrogen atoms, and a carbon-nitrogen group. It isnoted that a bridge always converts a monocyclic ring into a tricyclicring. When a ring is bridged, the substituents recited for the ring mayalso be present on the bridge.

The term “counterion” is used to represent a negatively charged speciessuch as chloride, bromide, hydroxide, acetate, and sulfate.

When a dotted ring is used within a ring structure, this indicates thatthe ring structure may be saturated, partially saturated or unsaturated.

As referred to herein, the term “substituted” means that at least onehydrogen atom is replaced with a non-hydrogen group, provided thatnormal valencies are maintained and that the substitution results in astable compound. When a substituent is keto (i.e., ═O), then 2 hydrogenson the atom are replaced. Keto substituents are not present on aromaticmoieties. When a ring system (e.g., carbocyclic or heterocyclic) is saidto be substituted with a carbonyl group or a double bond, it is intendedthat the carbonyl group or double bond be part (i.e., within) of thering. Ring double bonds, as used herein, are double bonds that areformed between two adjacent ring atoms (e.g., C═C, C═N, or N═N).

In cases wherein there are nitrogen atoms (e.g., amines) on compounds ofthe present invention, these may be converted to N-oxides by treatmentwith an oxidizing agent (e.g., mCPBA and/or hydrogen peroxides) toafford other compounds of this invention. Thus, shown and claimednitrogen atoms are considered to cover both the shown nitrogen and itsN-oxide (N→O) derivative.

When any variable occurs more than one time in any constituent orformula for a compound, its definition at each occurrence is independentof its definition at every other occurrence. Thus, for example, if agroup is shown to be substituted with 0-3 R groups, then said group mayoptionally be substituted with up to three R groups, and at eachoccurrence R is selected independently from the definition of R. Also,combinations of substituents and/or variables are permissible only ifsuch combinations result in stable compounds.

When a bond to a substituent is shown to cross a bond connecting twoatoms in a ring, then such substituent may be bonded to any atom on thering. When a substituent is listed without indicating the atom in whichsuch substituent is bonded to the rest of the compound of a givenformula, then such substituent may be bonded via any atom in suchsubstituent. Combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms that are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, and/or other problem or complication,commensurate with a reasonable benefit/risk ratio.

As used herein, “pharmaceutically acceptable salts” refer to derivativesof the disclosed compounds wherein the parent compound is modified bymaking acid or base salts thereof. Examples of pharmaceuticallyacceptable salts include, but are not limited to, mineral or organicacid salts of basic groups such as amines; and alkali or organic saltsof acidic groups such as carboxylic acids. The pharmaceuticallyacceptable salts include the conventional non-toxic salts or thequaternary ammonium salts of the parent compound formed, for example,from non-toxic inorganic or organic acids. For example, suchconventional non-toxic salts include those derived from inorganic acidssuch as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, andnitric; and the salts prepared from organic acids such as acetic,propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric,ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic,benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric,toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, andisethionic.

The pharmaceutically acceptable salts of the present invention can besynthesized from the parent compound that contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha stoichiometric amount of the appropriate base or acid in water or inan organic solvent, or in a mixture of the two; generally, nonaqueousmedia like ether, ethyl acetate, ethanol, isopropanol, or acetonitrileare preferred. Lists of suitable salts are found in Remington'sPharmaceutical Sciences, 18th Edition, Mack Publishing Company, Easton,Pa. (1990), the disclosure of which is hereby incorporated by reference.

In addition, compounds of formula I may have prodrug forms. Any compoundthat will be converted in vivo to provide the bioactive agent (i.e., acompound of formula I) is a prodrug within the scope and spirit of theinvention. Various forms of prodrugs are well known in the art. Forexamples of such prodrug derivatives, see:

-   a) Bundgaard, H., ed., Design of Prodrugs, Elsevier (1985), and    Widder, K. et al., eds., Methods in Enzymology, 112:309-396,    Academic Press (1985);-   b) Bundgaard, H., Chapter 5: “Design and Application of Prodrugs”, A    Textbook of Drug Design and Development, pp. 113-191,    Krosgaard-Larsen, P. et al., eds., Harwood Academic Publishers    (1991);-   c) Bundgaard, H., Adv. Drug Deliv. Rev., 8:1-38 (1992);-   d) Bundgaard, H. et al., J. Pharm. Sci., 77:285 (1988); and-   e) Kakeya, N. et al., Chem. Pharm. Bull., 32:692 (1984).

Compounds containing a carboxy group can form physiologicallyhydrolyzable esters that serve as prodrugs by being hydrolyzed in thebody to yield formula I compounds per se. Such prodrugs are preferablyadministered orally since hydrolysis in many instances occursprincipally under the influence of the digestive enzymes. Parenteraladministration may be used where the ester per se is active, or in thoseinstances where hydrolysis occurs in the blood. Examples ofphysiologically hydrolyzable esters of compounds of formula I includeC₁₋₆alkyl, C₁₋₆alkylbenzyl, 4-methoxybenzyl, indanyl, phthalyl,methoxymethyl, C₁₋₆ alkanoyloxy-C₁₋₆alkyl (e.g., acetoxymethyl,pivaloyloxymethyl or propionyloxymethyl),C₁₋₆alkoxycarbonyloxy-C₁₋₆alkyl (e.g., methoxycarbonyl-oxymethyl orethoxycarbonyloxymethyl, glycyloxymethyl, phenylglycyloxymethyl,(5-methyl-2-oxo-1,3-dioxolen-4-yl)-methyl), and other well knownphysiologically hydrolyzable esters used, for example, in the penicillinand cephalosporin arts. Such esters may be prepared by conventionaltechniques known in the art.

Preparation of prodrugs is well known in the art and described in, forexample, King, F. D., ed., Medicinal Chemistry: Principles and Practice,The Royal Society of Chemistry, Cambridge, UK (1994); Testa, B. et al.,Hydrolysis in Drug and Prodrug Metabolism. Chemistry, Biochemistry andEnzymology, VCHA and Wiley-VCH, Zurich, Switzerland (2003); Wermuth, C.G., ed., The Practice of Medicinal Chemistry, Academic Press, San Diego,Calif. (1999).

The present invention is intended to include all isotopes of atomsoccurring in the present compounds. Isotopes include those atoms havingthe same atomic number but different mass numbers. By way of generalexample and without limitation, isotopes of hydrogen include deuteriumand tritium. Deuterium has one proton and one neutron in its nucleus andthat has twice the mass of ordinary hydrogen. Deuterium can berepresented by symbols such as “²H” or “D”. The term “deuterated”herein, by itself or used to modify a compound or group, refers toreplacement of one or more hydrogen atom(s), which is attached tocarbon(s), with a deuterium atom. Isotopes of carbon include ¹³C and¹⁴C.

Isotopically-labeled compounds of the invention can generally beprepared by conventional techniques known to those skilled in the art orby processes analogous to those described herein, using an appropriateisotopically-labeled reagent in place of the non-labeled reagentotherwise employed. Such compounds have a variety of potential uses,e.g., as standards and reagents in determining the ability of apotential pharmaceutical compound to bind to target proteins orreceptors, or for imaging compounds of this invention bound tobiological receptors in vivo or in vitro.

“Stable compound” and “stable structure” are meant to indicate acompound that is sufficiently robust to survive isolation to a usefuldegree of purity from a reaction mixture, and formulation into anefficacious therapeutic agent. It is preferred that compounds of thepresent invention do not contain a N-halo, S(O)₂H, or S(O)H group.

The term “solvate” means a physical association of a compound of thisinvention with one or more solvent molecules, whether organic orinorganic. This physical association includes hydrogen bonding. Incertain instances the solvate will be capable of isolation, for examplewhen one or more solvent molecules are incorporated in the crystallattice of the crystalline solid. The solvent molecules in the solvatemay be present in a regular arrangement and/or a non-orderedarrangement. The solvate may comprise either a stoichiometric ornonstoichiometric amount of the solvent molecules. “Solvate” encompassesboth solution-phase and isolable solvates. Exemplary solvates include,but are not limited to, hydrates, ethanolates, methanolates, andisopropanolates. Methods of solvation are generally known in the art.

Abbreviations as used herein, are defined as follows: “1×” for once,“2×” for twice, “3×” for thrice, “° C.” for degrees Celsius, “eq” forequivalent or equivalents, “g” for gram or grams, “mg” for milligram ormilligrams, “L” for liter or liters, “mL” for milliliter or milliliters,“μL” for microliter or microliters, “N” for normal, “M” for molar,“mmol” for millimole or millimoles, “min” for minute or minutes, “h” forhour or hours, “rt” for room temperature, “RT” for retention time, “RBF”for round bottom flask, “atm” for atmosphere, “psi” for pounds persquare inch, “conc.” for concentrate, “RCM” for ring-closing metathesis,“sat” or “sat'd” for saturated, “SFC” for supercritical fluidchromatography “MW” for molecular weight, “mp” for melting point, “ee”for enantiomeric excess, “MS” or “Mass Spec” for mass spectrometry,“ESI” for electrospray ionization mass spectroscopy, “HR” for highresolution, “HRMS” for high resolution mass spectrometry, “LCMS” forliquid chromatography mass spectrometry, “HPLC” for high pressure liquidchromatography, “RP HPLC” for reverse phase HPLC, “TLC” or “tlc” forthin layer chromatography, “NMR” for nuclear magnetic resonancespectroscopy, “nOe” for nuclear Overhauser effect spectroscopy, “¹H” forproton, “δ” for delta, “s” for singlet, “d” for doublet, “t” fortriplet, “q” for quartet, “m” for multiplet, “br” for broad, “Hz” forhertz, and “α”, “β”, “R”, “S”, “E”, and “Z” are stereochemicaldesignations familiar to one skilled in the art.

-   Me methyl-   Et ethyl-   Pr propyl-   i-Pr isopropyl-   Bu butyl-   i-Bu isobutyl-   t-Bu tert-butyl-   Ph phenyl-   Bn benzyl-   Boc or BOC tert-butyloxycarbonyl-   Boc₂O di-tert-butyl dicarbonate-   AcOH or HOAc acetic acid-   AlCl₃ aluminum chloride-   AIBN azobisisobutyronitrile-   aqueous aq-   BBr₃ boron tribromide-   BCl₃ boron trichloride-   BEMP    2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorine-   BOP reagent benzotriazol-1-yloxytris(dimethylamino)phosphonium    hexafluorophosphate-   Burgess reagent 1-methoxy-N-triethylammoniosulfonyl-methanimidate-   Cbz carbobenzyloxy-   DCM or CH₂Cl₂ dichloromethane-   CH₃CN or ACN acetonitrile-   CDCl₃ deutero-chloroform-   CHCl₃ chloroform-   mCPBA or m-CPBA meta-chloroperbenzoic acid-   Cs₂CO₃ cesium carbonate-   Cu(OAc)₂ copper (II) acetate-   CuI copper(I) iodide-   CuSO₄ copper(II) sulfate-   Cy₂NMe N-cyclohexyl-N-methylcyclohexanamine-   DBU 1,8-diazabicyclo[5.4.0]undec-7-ene-   DCE 1,2-dichloroethane-   DEA diethylamine-   Dess-Martin    1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-beniziodoxol-3-(1H)-one-   DIC or DIPCDI diisopropylcarbodiimide-   DIEA, DIPEA or Hunig's base diisopropylethylamine-   DMAP 4-dimethylaminopyridine-   DME 1,2-dimethoxyethane-   DMF dimethyl formamide-   DMSO dimethyl sulfoxide-   cDNA complimentary DNA-   Dppp (R)-(+)-1,2-bis(diphenylphosphino)propane-   DuPhos (+)-1,2-bis((2S,5S)-2,5-diethylphospholano)benzene-   EDC N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide-   EDCI N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride-   EDTA ethylenediaminetetraacetic acid-   (S,S)-EtDuPhosRh(I)    (+)-1,2-bis((2S,5S)-2,5-diethylphospholano)benzene(1,5-cyclooctadiene)rhodium(I)    trifluoromethanesulfonate-   Et₃N or TEA triethylamine-   EtOAc ethyl acetate-   Et₂O diethyl ether-   EtOH ethanol-   GMF glass microfiber filter-   Grubbs II    (1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene)dichloro(phenylmethylene)(triycyclohexylphosphine)ruthenium-   HCl hydrochloric acid-   HATU O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium    hexafluorophosphate-   HEPES 4-(2-hydroxyethyl)piperazine-1-ethanesulfonic acid-   Hex hexane-   HOBt or HOBT 1-hydroxybenzotriazole-   H₂O₂ hydrogen peroxide-   H₂SO₄ sulfuric acid-   IBX 2-iodoxybenzoic acid-   InCl₃ Indium(III) chloride-   Jones reagent CrO₃ in aqueous H₂SO₄, 2 M-   K₂CO₃ potassium carbonate-   K₂HPO₄ potassium phosphate dibasic-   K₃PO₄ potassium phosphate tribasic-   KOAc potassium acetate-   K₃PO₄ potassium phosphate-   LAH lithium aluminum hydride-   LG leaving group-   LiOH lithium hydroxide-   MeOH methanol-   MgSO₄ magnesium sulfate-   MsOH or MSA methylsulfonic acid-   NaCl sodium chloride-   NaH sodium hydride-   NaHCO₃ sodium bicarbonate-   Na₂CO₃ sodium carbonate-   NaOH sodium hydroxide-   Na₂SO₃ sodium sulfite-   Na₂SO₄ sodium sulfate-   NBS N-bromosuccinimide-   NCS N-chlorosuccinimide-   NH₃ ammonia-   NH₄Cl ammonium chloride-   NH₄OH ammonium hydroxide-   NH₄COOH ammonium formate-   NMM N-methylmorpholine-   OTf triflate or trifluoromethanesulfonate-   Pd₂(dba)₃ tris(dibenzylideneacetone)dipalladium(0)-   Pd(OAc)₂ palladium(II) acetate-   Pd/C palladium on carbon-   Pd(dppf)Cl₂    [1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II)-   Ph₃PCl₂ triphenylphosphine dichloride-   PG protecting group-   POCl₃ phosphorus oxychloride-   i-PrOH or IPA isopropanol-   PS Polystyrene-   rt room temperature-   SEM-Cl 2-(trimethysilyl)ethoxymethyl chloride-   SiO₂ silica oxide-   SnCl₂ tin(II) chloride-   TBAI tetra-n-butylammonium iodide-   TBN t-butyl nitrite-   TFA trifluoroacetic acid-   THF tetrahydrofuran-   TMSCHN₂ trimethylsilyldiazomethane-   T3P® propane phosphonic acid anhydride-   TRIS tris (hydroxymethyl) aminomethane-   pTsOH p-toluenesulfonic acid

The compounds of the present invention can be prepared in a number ofways known to one skilled in the art of organic synthesis, which aredescribed in more detail in Section VI.

IV. Biology

While blood coagulation is essential to the regulation of an organism'shemostasis, it is also involved in many pathological conditions. Inthrombosis, a blood clot, or thrombus, may form and obstruct circulationlocally, causing ischemia and organ damage. Alternatively, in a processknown as embolism, the clot may dislodge and subsequently become trappedin a distal vessel, where it again causes ischemia and organ damage.Diseases arising from pathological thrombus formation are collectivelyreferred to as thromboembolic disorders and include acute coronarysyndrome, unstable angina, myocardial infarction, atrial fibrillation,thrombosis in the cavity of the heart, ischemic stroke, deep veinthrombosis, peripheral occlusive arterial disease, transient ischemicattack, and pulmonary embolism. In addition, thrombosis occurs onartificial surfaces in contact with blood, including catheters, stents,artificial heart valves, and hemodialysis membranes.

Some conditions contribute to the risk of developing thrombosis. Forexample, alterations of the vessel wall, changes in the flow of blood,and alterations in the composition of the vascular compartment. Theserisk factors are collectively known as Virchow's triad. (Colman, R. W.et al., eds., Hemostasis and Thrombosis, Basic Principles and ClinicalPractice, Fifth Edition, p. 853, Lippincott Williams & Wilkins (2006)).

Antithrombotic agents are frequently given to patients at risk ofdeveloping thromboembolic disease because of the presence of one or morepredisposing risk factors from Virchow's triad to prevent formation ofan occlusive thrombus (primary prevention). For example, in anorthopedic surgery setting (e.g., hip and knee replacement), anantithrombotic agent is frequently administered prior to a surgicalprocedure. The antithrombotic agent counterbalances the prothromboticstimulus exerted by vascular flow alterations (stasis), potentialsurgical vessel wall injury, as well as changes in the composition ofthe blood due to the acute phase response related to surgery. Anotherexample of the use of an antithrombotic agent for primary prevention isdosing with aspirin, a platelet activation inhibitor, in patients atrisk for developing thrombotic cardiovascular disease. Well recognizedrisk factors in this setting include age, male gender, hypertension,diabetes mellitus, lipid alterations, and obesity.

Antithrombotic agents are also indicated for secondary prevention,following an initial thrombotic episode. For example, patients withmutations in factor V (also known as factor V Leiden) and additionalrisk factors (e.g., pregnancy), are dosed with anticoagulants to preventthe reoccurrence of venous thrombosis. Another example entails secondaryprevention of cardiovascular events in patients with a history of acutemyocardial infarction or acute coronary syndrome. In a clinical setting,a combination of aspirin and clopidogrel (or other thienopyridines) maybe used to prevent a second thrombotic event.

Antithrombotic agents are also given to treat the disease state (i.e.,by arresting its development) after it has already started. For example,patients presenting with deep vein thrombosis are treated withanticoagulants (i.e., heparin, warfarin, or LMWH) to prevent furthergrowth of the venous occlusion. Over time, these agents also cause aregression of the disease state because the balance betweenprothrombotic factors and anticoagulant/profibrinolytic pathways ischanged in favor of the latter. Examples on the arterial vascular bedinclude the treatment of patients with acute myocardial infarction oracute coronary syndrome with aspirin and clopidogrel to prevent furthergrowth of vascular occlusions and eventually leading to a regression ofthrombotic occlusions.

Thus, antithrombotic agents are used widely for primary and secondaryprevention (i.e., prophylaxis or risk reduction) of thromboembolicdisorders, as well as treatment of an already existing thromboticprocess. Drugs that inhibit blood coagulation, or anticoagulants, are“pivotal agents for prevention and treatment of thromboembolicdisorders” (Hirsh, J. et al., Blood, 105:453-463 (2005)).

An alternative way of initiation of coagulation is operative when bloodis exposed to artificial surfaces (e.g., during hemodialysis, “on-pump”cardiovascular surgery, vessel grafts, bacterial sepsis), on cellsurfaces, cellular receptors, cell debris, DNA, RNA, and extracellularmatrices. This process is also termed contact activation. Surfaceabsorption of factor XII leads to a conformational change in the factorXII molecule, thereby facilitating activation to proteolytic activefactor XII molecules (factor XIIa and factor XIIf). Factor XIIa (orXIIf) has a number of target proteins, including plasma prekallikreinand factor XI. Active plasma kallikrein further activates factor XII,leading to an amplification of contact activation. Alternatively, theserine protease prolylcarboxylpeptidase can activate plasma kallikreincomplexed with high molecular weight kininogen in a multiprotein complexformed on the surface of cells and matrices (Shariat-Madar et al.,Blood, 108:192-199 (2006)). Contact activation is a surface mediatedprocess responsible in part for the regulation of thrombosis andinflammation, and is mediated, at least in part, by fibrinolytic-,complement-, kininogen/kinin-, and other humoral and cellular pathways(for review, Coleman, R., “Contact Activation Pathway”, Hemostasis andThrombosis, pp. 103-122, Lippincott Williams & Wilkins (2001); Schmaier,A. H., “Contact Activation”, Thrombosis and Hemorrhage, pp. 105-128(1998)). The biological relevance of the contact activation system forthromboembolic diseases is supported by the phenotype of factor XIIdeficient mice. More specifically, factor XII deficient mice wereprotected from thrombotic vascular occlusion in several thrombosismodels as well as stroke models and the phenotype of the XII deficientmice was identical to XI deficient mice (Renne et al., J. Exp. Med.,202:271-281 (2005); Kleinschmitz et al., J. Exp. Med., 203:513-518(2006)). The fact that factor XI is down-stream from factor XIIa,combined with the identical phenotype of the XII and XI deficient micesuggest that the contact activation system could play a major role infactor XI activation in vivo.

Factor XI is a zymogen of a trypsin-like serine protease and is presentin plasma at a relatively low concentration. Proteolytic activation atan internal R369-I370 bond yields a heavy chain (369 amino acids) and alight chain (238 amino acids). The latter contains a typicaltrypsin-like catalytic triad (H₄₁₃, D464, and S557). Activation offactor XI by thrombin is believed to occur on negatively chargedsurfaces, most likely on the surface of activated platelets. Plateletscontain high affinity (0.8 nM) specific sites (130-500/platelet) foractivated factor XI. After activation, factor XIa remains surface boundand recognizes factor IX as its normal macromolecular substrate.(Galiani, D., Trends Cardiovasc. Med., 10:198-204 (2000)).

In addition to the feedback activation mechanisms described above,thrombin activates thrombin activated fibrinolysis inhibitor (TAFI), aplasma carboxypeptidase that cleaves C-terminal lysine and arginineresidues on fibrin, reducing the ability of fibrin to enhancetissue-type plasminogen activator (tPA) dependent plasminogenactivation. In the presence of antibodies to FXIa, clot lysis can occurmore rapidly independent of plasma TAFI concentration. (Bouma, B. N. etal., Thromb. Res., 101:329-354 (2001).) Thus, inhibitors of factor XIaare expected to be anticoagulant and profibrinolytic.

Further evidence for the anti-thromboembolic effects of targeting factorXI is derived from mice deficient in factor XI. It has been demonstratedthat complete fXI deficiency protected mice from ferric chloride(FeCl₃)-induced carotid artery thrombosis (Rosen et al., Thromb.Haemost., 87:774-777 (2002); Wang et al., J. Thromb. Haemost., 3:695-702(2005)). Also, factor XI deficiency rescues the perinatal lethalphenotype of complete protein C deficiency (Chan et al., Amer. J.Pathology, 158:469-479 (2001)). Furthermore, baboon cross-reactive,function blocking antibodies to human factor XI protect against baboonarterial—venous shunt thrombosis (Gruber et al., Blood, 102:953-955(2003)). Evidence for an antithrombotic effect of small moleculeinhibitors of factor XIa is also disclosed in published U.S. PatentPublication No. 2004/0180855 A1. Taken together, these studies suggestthat targeting factor XI will reduce the propensity for thrombotic andthromboembolic diseases.

Genetic evidence indicates that factor XI is not required for normalhomeostasis, implying a superior safety profile of the factor XImechanism compared to competing antithrombotic mechanisms. In contrastto hemophilia A (factor VIII deficiency) or hemophilia B (factor IXdeficiency), mutations of the factor XI gene causing factor XIdeficiency (hemophilia C) result in only a mild to moderate bleedingdiathesis characterized primarily by postoperative or posttraumatic, butrarely spontaneous hemorrhage. Postoperative bleeding occurs mostly intissue with high concentrations of endogenous fibrinolytic activity(e.g., oral cavity, and urogenital system). The majority of the casesare fortuitously identified by preoperative prolongation of aPTT(intrinsic system) without any prior bleeding history.

The increased safety of inhibition of XIa as an anticoagulation therapyis further supported by the fact that Factor XI knock-out mice, whichhave no detectable factor XI protein, undergo normal development, andhave a normal life span. No evidence for spontaneous bleeding has beennoted. The aPTT (intrinsic system) is prolonged in a gene dose-dependentfashion. Interestingly, even after severe stimulation of the coagulationsystem (tail transection), the bleeding time is not significantlyprolonged compared to wild-type and heterozygous litter mates. (Gailani,D., Frontiers in Bioscience, 6:201-207 (2001); Gailani, D. et al., BloodCoagulation and Fibrinolysis, 8:134-144 (1997).) Taken together, theseobservations suggest that high levels of inhibition of factor XIa shouldbe well tolerated. This is in contrast to gene targeting experimentswith other coagulation factors, excluding factor XII.

In vivo activation of factor XI can be determined by complex formationwith either C1 inhibitor or alpha 1 antitrypsin. In a study of 50patients with acute myocardial infarction (AMI), approximately 25% ofthe patients had values above the upper normal range of the complexELISA. This study can be viewed as evidence that at least in asubpopulation of patients with AMI, factor XI activation contributes tothrombin formation (Minnema, M. C. et al., Arterioscler. Thromb. Vasc.Biol., 20:2489-2493 (2000)). A second study establishes a positivecorrelation between the extent of coronary arteriosclerosis and factorXIa in complex with alpha 1 antitrypsin (Murakami, T. et al.,Arterioscler. Thromb. Vasc. Biol., 15:1107-1113 (1995)). In anotherstudy, Factor XI levels above the 90th percentile in patients wereassociated with a 2.2-fold increased risk for venous thrombosis(Meijers, J. C. M. et al., N. Engl. J. Med., 342:696-701 (2000)).

Also, it is preferred to find new compounds with improved activity in invitro clotting assays, compared with known serine protease inhibitors,such as the activated partial thromboplastin time (aPTT) or prothrombintime (PT) assay. (for a description of the aPTT and PT assays see,Goodnight, S. H. et al., “Screening Tests of Hemostasis”, Disorders ofThrombosis and Hemostasis: A Clinical Guide, Second Edition, pp. 41-51,McGraw-Hill, New York (2001)).

It is also desirable and preferable to find compounds with advantageousand improved characteristics compared with known serine proteaseinhibitors, in one or more of the following categories that are given asexamples, and are not intended to be limiting: (a) pharmacokineticproperties, including oral bioavailability, half life, and clearance;(b) pharmaceutical properties; (c) dosage requirements; (d) factors thatdecrease blood concentration peak-to-trough characteristics; (e) factorsthat increase the concentration of active drug at the receptor; (f)factors that decrease the liability for clinical drug-drug interactions;(g) factors that decrease the potential for adverse side-effects,including selectivity versus other biological targets; and (h) factorsthat improve manufacturing costs or feasibility.

Pre-clinical studies demonstrated significant antithrombotic effects ofsmall molecule factor XIa inhibitors in rabbit and rat model of arterialand venous thrombosis, at doses that preserved hemostasis. (Wong P. C.et al., Journal of Thrombosis and Thrombolysis, 32(2):129-137 (August2011); Schumacher, W. et al., Journal of Thrombosis and Haemostasis,3(Suppl. 1):P1228 (2005); Schumacher, W. A. et al., Eur. J Pharmacol.,167-174 (2007)). Furthermore, it was observed that in vitro prolongationof the aPTT by specific XIa inhibitors is a good predictor of efficacyin our thrombosis models. Thus, the in vitro aPTT test can be used as asurrogate for efficacy in vivo. Pre-clinical and clinical studies usingFXI antisense (ASO) has been shown to be effective in various venous andarterial thrombosis models, comparable to warfarin or enoxaparin withoutincreased bleeding (Bueller et al., DOI: 10.1056/NEJMoa1405760 (2014)).

As used herein, the term “patient” encompasses all mammalian species.

As used herein, “treating” or “treatment” cover the treatment of adisease-state in a mammal, particularly in a human, and include: (a)inhibiting the disease-state, i.e., arresting it development; and/or (b)relieving the disease-state, i.e., causing regression of the diseasestate.

As used herein, “prophylaxis” is the protective treatment of a diseasestate to reduce and/or minimize the risk and/or reduction in the risk ofrecurrence of a disease state by administering to a patient atherapeutically effective amount of at least one of the compounds of thepresent invention or a or a stereoisomer, a tautomer, a pharmaceuticallyacceptable salt, or a solvate thereof. Patients may be selected forprophylaxis therapy based on factors that are known to increase risk ofsuffering a clinical disease state compared to the general population.For prophylaxis treatment, conditions of the clinical disease state mayor may not be presented yet. “Prophylaxis” treatment can be divided into(a) primary prophylaxis and (b) secondary prophylaxis. Primaryprophylaxis is defined as treatment to reduce or minimize the risk of adisease state in a patient that has not yet presented with a clinicaldisease state, whereas secondary prophylaxis is defined as minimizing orreducing the risk of a recurrence or second occurrence of the same orsimilar clinical disease state.

As used herein, “prevention” cover the preventive treatment of asubclinical disease-state in a mammal, particularly in a human, aimed atreducing the probability of the occurrence of a clinical disease-state.Patients are selected for preventative therapy based on factors that areknown to increase risk of suffering a clinical disease state compared tothe general population.

As used herein, “risk reduction” covers therapies that lower theincidence of development of a clinical disease state. As such, primaryand secondary prevention therapies are examples of risk reduction.

“Therapeutically effective amount” is intended to include an amount of acompound of the present invention that is effective when administeredalone or in combination to inhibit factor XIa and/or plasma kallikreinand/or to prevent or treat the disorders listed herein. When applied toa combination, the term refers to combined amounts of the activeingredients that result in the preventive or therapeutic effect, whetheradministered in combination, serially, or simultaneously.

The term “thrombosis”, as used herein, refers to formation or presenceof a thrombus (pl. thrombi); clotting within a blood vessel that maycause ischemia or infarction of tissues supplied by the vessel. The term“embolism”, as used herein, refers to sudden blocking of an artery by aclot or foreign material that has been brought to its site of lodgmentby the blood current. The term “thromboembolism”, as used herein, refersto obstruction of a blood vessel with thrombotic material carried by theblood stream from the site of origin to plug another vessel. The term“thromboembolic disorders” entails both “thrombotic” and “embolic”disorders (defined above).

The term “thromboembolic disorders” as used herein includes arterialcardiovascular thromboembolic disorders, venous cardiovascular orcerebrovascular thromboembolic disorders, and thromboembolic disordersin the chambers of the heart or in the peripheral circulation. The term“thromboembolic disorders” as used herein also includes specificdisorders selected from, but not limited to, unstable angina or otheracute coronary syndromes, atrial fibrillation, first or recurrentmyocardial infarction, ischemic sudden death, transient ischemic attack,stroke, atherosclerosis, peripheral occlusive arterial disease, venousthrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism,coronary arterial thrombosis, cerebral arterial thrombosis, cerebralembolism, kidney embolism, pulmonary embolism, and thrombosis resultingfrom medical implants, devices, or procedures in which blood is exposedto an artificial surface that promotes thrombosis. The medical implantsor devices include, but are not limited to: prosthetic valves,artificial valves, indwelling catheters, stents, blood oxygenators,shunts, vascular access ports, ventricular assist devices and artificialhearts or heart chambers, and vessel grafts. The procedures include, butare not limited to: cardiopulmonary bypass, percutaneous coronaryintervention, and hemodialysis. In another embodiment, the term“thromboembolic disorders” includes acute coronary syndrome, stroke,deep vein thrombosis, and pulmonary embolism.

In another embodiment, the present invention provides a method for thetreatment of a thromboembolic disorder, wherein the thromboembolicdisorder is selected from unstable angina, an acute coronary syndrome,atrial fibrillation, myocardial infarction, transient ischemic attack,stroke, atherosclerosis, peripheral occlusive arterial disease, venousthrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism,coronary arterial thrombosis, cerebral arterial thrombosis, cerebralembolism, kidney embolism, pulmonary embolism, and thrombosis resultingfrom medical implants, devices, or procedures in which blood is exposedto an artificial surface that promotes thrombosis. In anotherembodiment, the present invention provides a method for the treatment ofa thromboembolic disorder, wherein the thromboembolic disorder isselected from acute coronary syndrome, stroke, venous thrombosis, atrialfibrillation, and thrombosis resulting from medical implants anddevices.

In another embodiment, the present invention provides a method for theprimary prophylaxis of a thromboembolic disorder, wherein thethromboembolic disorder is selected from unstable angina, an acutecoronary syndrome, atrial fibrillation, myocardial infarction, ischemicsudden death, transient ischemic attack, stroke, atherosclerosis,peripheral occlusive arterial disease, venous thrombosis, deep veinthrombosis, thrombophlebitis, arterial embolism, coronary arterialthrombosis, cerebral arterial thrombosis, cerebral embolism, kidneyembolism, pulmonary embolism, and thrombosis resulting from medicalimplants, devices, or procedures in which blood is exposed to anartificial surface that promotes thrombosis. In another embodiment, thepresent invention provides a method for the primary prophylaxis of athromboembolic disorder, wherein the thromboembolic disorder is selectedfrom acute coronary syndrome, stroke, venous thrombosis, and thrombosisresulting from medical implants and devices.

In another embodiment, the present invention provides a method for thesecondary prophylaxis of a thromboembolic disorder, wherein thethromboembolic disorder is selected from unstable angina, an acutecoronary syndrome, atrial fibrillation, recurrent myocardial infarction,transient ischemic attack, stroke, atherosclerosis, peripheral occlusivearterial disease, venous thrombosis, deep vein thrombosis,thrombophlebitis, arterial embolism, coronary arterial thrombosis,cerebral arterial thrombosis, cerebral embolism, kidney embolism,pulmonary embolism, and thrombosis resulting from medical implants,devices, or procedures in which blood is exposed to an artificialsurface that promotes thrombosis. In another embodiment, the presentinvention provides a method for the secondary prophylaxis of athromboembolic disorder, wherein the thromboembolic disorder is selectedfrom acute coronary syndrome, stroke, atrial fibrillation and venousthrombosis.

The term “stroke”, as used herein, refers to embolic stroke oratherothrombotic stroke arising from occlusive thrombosis in the carotidcommunis, carotid interna, or intracerebral arteries.

It is noted that thrombosis includes vessel occlusion (e.g., after abypass) and reocclusion (e.g., during or after percutaneous transluminalcoronary angioplasty). The thromboembolic disorders may result fromconditions including but not limited to atherosclerosis, surgery orsurgical complications, prolonged immobilization, arterial fibrillation,congenital thrombophilia, cancer, diabetes, effects of medications orhormones, and complications of pregnancy.

Thromboembolic disorders are frequently associated with patients withatherosclerosis. Risk factors for atherosclerosis include but are notlimited to male gender, age, hypertension, lipid disorders, and diabetesmellitus. Risk factors for atherosclerosis are at the same time riskfactors for complications of atherosclerosis, i.e., thromboembolicdisorders.

Similarly, arterial fibrillation is frequently associated withthromboembolic disorders. Risk factors for arterial fibrillation andsubsequent thromboembolic disorders include cardiovascular disease,rheumatic heart disease, nonrheumatic mitral valve disease, hypertensivecardiovascular disease, chronic lung disease, and a variety ofmiscellaneous cardiac abnormalities as well as thyrotoxicosis.

Diabetes mellitus is frequently associated with atherosclerosis andthromboembolic disorders. Risk factors for the more common type 2include but are not limited to are family history, obesity, physicalinactivity, race/ethnicity, previously impaired fasting glucose orglucose tolerance test, history of gestational diabetes mellitus ordelivery of a “big baby”, hypertension, low HDL cholesterol, andpolycystic ovary syndrome.

Risk factors for congenital thrombophilia include gain of functionmutations in coagulation factors or loss of function mutations in theanticoagulant- or fibrinolytic pathways.

Thrombosis has been associated with a variety of tumor types, e.g.,pancreatic cancer, breast cancer, brain tumors, lung cancer, ovariancancer, prostate cancer, gastrointestinal malignancies, and Hodgkins ornon-Hodgkins lymphoma. Recent studies suggest that the frequency ofcancer in patients with thrombosis reflects the frequency of aparticular cancer type in the general population (Levitan, N. et al.,Medicine (Baltimore), 78(5):285-291 (1999); Levine M. et al., N. Engl. JMed., 334(11):677-681 (1996); Blom, J. W. et al., JAMA, 293(6):715-722(2005)). Hence, the most common cancers associated with thrombosis inmen are prostate, colorectal, brain, and lung cancer, and in women arebreast, ovary, and lung cancer. The observed rate of venousthromboembolism (VTE) in cancer patients is significant. The varyingrates of VTE between different tumor types are most likely related tothe selection of the patient population. Cancer patients at risk forthrombosis may possess any or all of the following risk factors: (i) thestage of the cancer (i.e., presence of metastases), (ii) the presence ofcentral vein catheters, (iii) surgery and anticancer therapies includingchemotherapy, and (iv) hormones and antiangiogenic drugs. Thus, it iscommon clinical practice to dose patients having advanced tumors withheparin or low molecular heparin to prevent thromboembolic disorders. Anumber of low molecular heparin preparations have been approved by theFDA for these indications.

There are three main clinical situations when considering the preventionof VTE in a medical cancer patient: (i) the patient is bedridden forprolonged periods of time; (ii) the ambulatory patient is receivingchemotherapy or radiation; and (iii) the patient is with indwellingcentral vein catheters. Unfractionated heparin (UFH) and low molecularweight heparin (LMWH) are effective antithrombotic agents in cancerpatients undergoing surgery. (Mismetti, P. et al., British Journal ofSurgery, 88:913-930 (2001).)

A. In Vitro Assays

The effectiveness of compounds of the present invention as inhibitors ofthe coagulation Factors XIa, VIIa, IXa, Xa, XIIa, plasma kallikrein orthrombin, can be determined using a relevant purified serine protease,respectively, and an appropriate synthetic substrate. The rate ofhydrolysis of the chromogenic or fluorogenic substrate by the relevantserine protease was measured both in the absence and presence ofcompounds of the present invention. Hydrolysis of the substrate resultedin the release of pNA (para nitroaniline), which was monitoredspectrophotometrically by measuring the increase in absorbance at 405nm, or the release of AMC (amino methylcoumarin), which was monitoredspectrofluorometrically by measuring the increase in emission at 460 nmwith excitation at 380 nm. A decrease in the rate of absorbance orfluorescence change in the presence of inhibitor is indicative of enzymeinhibition. Such methods are known to one skilled in the art. Theresults of this assay are expressed as the inhibitory constant, K_(i).

Factor XIa determinations were made in 50 mM HEPES buffer at pH 7.4containing 145 mM NaCl, 5 mM KCl, and 0.1% PEG 8000 (polyethyleneglycol; JT Baker or Fisher Scientific). Determinations were made usingpurified human Factor XIa at a final concentration of 25-200 pM(Haematologic Technologies) and the synthetic substrate S-2366(pyroGlu-Pro-Arg-pNA; CHROMOGENIX® or AnaSpec) at a concentration of0.0002-0.001 M.

Factor VIIa determinations were made in 0.005 M calcium chloride, 0.15 Msodium chloride, 0.05 M HEPES buffer containing 0.1% PEG 8000 at a pH of7.5. Determinations were made using purified human Factor VIIa(Haematologic Technologies) or recombinant human Factor VIIa (NovoNordisk) at a final assay concentration of 0.5-10 nM, recombinantsoluble tissue factor at a concentration of 10-40 nM and the syntheticsubstrate H-D-Ile-Pro-Arg-pNA (S-2288; CHROMOGENIX® or BMPM-2; AnaSpec)at a concentration of 0.001-0.0075 M.

Factor IXa determinations were made in 0.005 M calcium chloride, 0.1 Msodium chloride, 0.0000001 M Refludan (Berlex), 0.05 M TRIS base and0.5% PEG 8000 at a pH of 7.4. Refludan was added to inhibit smallamounts of thrombin in the commercial preparations of human Factor IXa.Determinations were made using purified human Factor IXa (HaematologicTechnologies) at a final assay concentration of 20-100 nM and thesynthetic substrate PCIXA2100-B (CenterChem) or Pefafluor IXa 3688(H-D-Leu-Ph′Gly-Arg-AMC; CenterChem) at a concentration of 0.0004-0.0005M.

Factor Xa determinations were made in 0.1 M sodium phosphate buffer at apH of 7.5 containing 0.2 M sodium chloride and 0.5% PEG 8000.Determinations were made using purified human Factor Xa (HaematologicTechnologies) at a final assay concentration of 150-1000 pM and thesynthetic substrate S-2222 (Bz-Ile-Glu (gamma-OMe, 50%)—Gly-Arg-pNA;CHROMOGENIX®) at a concentration of 0.0002-0.00035 M.

Factor XIIa determinations were made in 0.05 M HEPES buffer at pH 7.4containing 0.145 M NaCl, 0.05 M KCl, and 0.1% PEG 8000. Determinationswere made using purified human Factor XIIa at a final concentration of 4nM (American Diagnostica) and the synthetic substrate SPECTROZYME® #312(H-D-CHT-Gly-L-Arg-pNA.2AcOH; American Diagnostica) at a concentrationof 0.00015 M.

Plasma kallikrein determinations were made in 0.1 M sodium phosphatebuffer at a pH of 7.5 containing 0.1-0.2 M sodium chloride and 0.5% PEG8000. Determinations were made using purified human plasma kallikrein(Enzyme Research Laboratories) at a final assay concentration of 200 pMand the synthetic substrate S-2302 (H-(D)-Pro-Phe-Arg-pNA; CHROMOGENIX®)at a concentration of 0.00008-0.0004 M.

Thrombin determinations were made in 0.1 M sodium phosphate buffer at apH of 7.5 containing 0.2 M sodium chloride and 0.5% PEG 8000.Determinations were made using purified human alpha thrombin(Haematologic Technologies or Enzyme Research Laboratories) at a finalassay concentration of 200-250 pM and the synthetic substrate S-2366(pyroGlu-Pro-Arg-pNA; CHROMOGENIX® or AnaSpec) at a concentration of0.0002-0.0004 M.

The Michaelis constant, K_(m), for substrate hydrolysis by eachprotease, was determined at 25° C. or 37° C. in the absence ofinhibitor. Values of K_(i) were determined by allowing the protease toreact with the substrate in the presence of the inhibitor. Reactionswere allowed to go for periods of 20-180 minutes (depending on theprotease) and the velocities (rate of absorbance or fluorescence changeversus time) were measured. The following relationships were used tocalculate K_(i) values:

(Vmax*S)/(K _(m) +S)

(v _(o) −v _(s))/v _(s) =I/(K _(i)(1+S/K _(m))) for a competitiveinhibitor with one binding site; or

v _(s) /v _(o) =A+(B−A)/(1+(I/IC ₅₀)^(n)); and

K _(i) =IC ₅₀/(1+S/K _(m)) for a competitive inhibitor

where:

v_(o) is the velocity of the control in the absence of inhibitor;

v_(s) is the velocity in the presence of inhibitor;

V_(max) is the maximum reaction velocity;

I is the concentration of inhibitor;

A is the minimum activity remaining (usually locked at zero);

B is the maximum activity remaining (usually locked at 1.0);

n is the Hill coefficient, a measure of the number and cooperativity ofpotential inhibitor binding sites;

IC₅₀ is the concentration of inhibitor that produces 50% inhibitionunder the assay conditions;

K_(i) is the dissociation constant of the enzyme: inhibitor complex;

S is the concentration of substrate; and

K_(m) is the Michaelis constant for the substrate.

The selectivity of a compound may be evaluated by taking the ratio ofthe K_(i) value for a given protease with the K_(i) value for theprotease of interest (i.e., selectivity for FXIa versus protease P=K_(i)for protease P/K_(i) for FXIa). Compounds with selectivity ratios>20 areconsidered selective.

The effectiveness of compounds of the present invention as inhibitors ofcoagulation can be determined using a standard or modified clottingassay. An increase in the plasma clotting time in the presence ofinhibitor is indicative of anticoagulation. Relative clotting time isthe clotting time in the presence of an inhibitor divided by theclotting time in the absence of an inhibitor. The results of this assaymay be expressed as IC1.5× or IC₂×, the inhibitor concentration requiredto increase the clotting time by 50 or 100 percent, respectively. TheIC1.5× or IC₂× is found by linear interpolation from relative clottingtime versus inhibitor concentration plots using inhibitor concentrationthat spans the IC1.5× or IC₂×.

Clotting times are determined using citrated normal human plasma as wellas plasma obtained from a number of laboratory animal species (e.g.,rat, or rabbit). A compound is diluted into plasma beginning with a 10mM DMSO stock solution. The final concentration of DMSO is less than 2%.Plasma clotting assays are performed in an automated coagulationanalyzer (SYSMEX®, Dade-Behring, Ill.). Similarly, clotting times can bedetermined from laboratory animal species or humans dosed with compoundsof the invention.

Activated Partial Thromboplastin Time (aPTT) is determined using ACTIN®FSL (Dade-Behring, Ill.) following the directions in the package insert.Plasma (0.05 mL) is warmed to 37° C. for 1 minute. ACTIN® FSL (0.05 mL)is added to the plasma and incubated for an additional 2 to 5 minutes.Calcium chloride (25 mM, 0.05 mL) is added to the reaction to initiatecoagulation. The clotting time is the time in seconds from the momentcalcium chloride is added until a clot is detected.

Prothrombin Time (PT) is determined using thromboplastin (ThromboplastinC Plus or INNOVIN®, Dade-Behring, Ill.) following the directions in thepackage insert. Plasma (0.05 mL) is warmed to 37° C. for 1 minute.Thromboplastin (0.1 mL) is added to the plasma to initiate coagulation.The clotting time is the time in seconds from the moment thromboplastinis added until a clot is detected.

Equilibrium solubilities were determined in various aqueous solventsbuffered to a specific pH. Approximately 1 mg of compound was used forequilibration in 100 to 300 μL of solvent. Samples were stirred at 300RPM at room temperature (20±2° C.) for 24 hours. If solubilization ofthe entire solid was observed, additional compound was added to keep thesolid in excess for the duration of the study. After 24 hours,microscopy was used to determine if there was a change in morphology tothe excess solid. The supernatants were then filtered through a 0.22 μmPVDF filter plate and diluted with acetonitrile for HPLC analysis.Calibration samples were also provided for HPLC analysis.

The extent to which compounds of the present invention bind to humanserum proteins can be determined using dialysis methods and analyticaltechniques well known in the art and described in, for example, Plise,E. G. et al., “Semi-automated protein binding methodology usingequilibrium dialysis and a novel mixed-matrix cassette approach”, J.Pharm. Sci., 99(12):5070-5078 (2010); Waters, N.J. et al., “Validationof a rapid equilibrium dialysis approach for the measurement of plasmaprotein binding”, J. Pharm. Sci., 97(10):4586-4595 (2008); Van Liempd,S. et al., “Development and Validation of a Higher-ThroughputEquilibrium Dialysis Assay for Plasma Protein Binding”, J. Lab. Autom.,16:56-67 (2011); Di, L. et al., “Impact of Recovery on Fraction UnboundUsing Equilibrium Dialysis”, J. Pharm. Sci., 101(3):1327-1335 (2011).

Compounds of the present invention were assayed in triplicate bycombining with human serum to achieve a final concentration of 10 μM.Dialysis was performed for 5 hours at 37° C., in a 10% CO₂ atmosphereagainst 0.133 M sodium phosphate buffer adjusted to pH 7.4 using thetwo-chamber Rapid Equilibrium Dialysis Assay Plates from Thermo Fisher(Waltham, Mass.). Assay samples from buffer and serum chambers werecollected at time zero (T₀[serum] and T_(0[Buffer])) and at 5 hourspost-incubation (T_(5h[Serum]) and T_(5h[Buffer])). Prior to analysis,dialyzed serum samples were diluted with 0.133 M sodium phosphate bufferadjusted to pH 7.4 and dialyzed buffer samples were diluted with humanserum to result in the same final serum concentration in each sample.Subsequently, these samples were extracted by protein precipitation inacetonitrile containing two analytical internal standards (200 nMalprenolol and 600 nM tolbutamide). Precipitated proteins andsupernatants were separated by centrifugation at 4000×g for 10 minutes.Sample supernatants were analyzed by LC-MS/MS and the peak area ratiosof compound to the internal standard were determined for initial timezero samples (T_(0[Serum]) and T_(0[Buffer])) and for post-equilibriumsamples (T_(5h[Serum]) and T_(5h[Buffer])). The percent free (freefraction), percent bound, and percent recovery results were calculatedas follows:

Percent free=100×(T _(5h[Buffer]) /T _(5h[Serum]))

Percent bound=100−percent free

Percent recovery=100×((T _(5h[Buffer]) +T _(5h[Serum]))/T _(0[Serum]))

Matrix interference was assessed by measuring the LC-MS/MS area ratio ofanalyte/internal standard for assay matrix blank (50:50 serum:buffer).The analytical conditions were deemed acceptable for assessment ofpercent free when the area ratio of analyte/internal standard for assaymatrix blank (50:50 serum:buffer) was less than 20% of the area ratiofor the T5h[Buffer] sample.

The exemplified Examples disclosed below were tested in the Factor XIaassay described above and found having Factor XIa inhibitory activity. Arange of Factor XIa inhibitory activity (Ki values) of ≤10 μM (10000 nM)was observed. Table 1 below lists Factor XIa Ki values measured at 37°C. for the following Examples.

TABLE 1 Example No. Factor XIa Ki (nM) 353 0.1 354 0.6 362 0.2 363 0.2367 0.1 368 0.1 369 0.1 370 0.1 371 0.1 372 0.2 373 0.2

The exemplified Examples disclosed below were tested in the PlasmaKallikrein assay described above and found having Plasma Kallikreininhibitory activity. A range of Plasma Kallikrein inhibitory activity(Ki values) of ≤10 μM (10000 nM) was observed. Table 2 below listsPlasma Kallikrein Ki values measured at 37° C. for the followingExamples.

TABLE 2 Example No. Plasma Kallikrein Ki (nM) 353 28 354 10 362 23 36322 367 24 368 32 369 33 370 17 371 19 372 35 373 37

The effectiveness of the compounds of the present invention asantithrombotic agents is also assessed in other assays such as aPTT,solubility, and human protein binding affinity described above. Comparedto the phenyl P2′ macrocycles disclosed in WO 2013/022814 and WO2014/022766, the pyrazolyl P2′ macrocycles of the present applicationexhibited surprising pharmacological activities. As shown in Table 3,the compounds of the present invention possess superior anticoagulantactivity, solubility and bioavailability compared to the referencecompounds.

TABLE 3 Human aPTT_(1.5x) Solubility at pH = protein binding Example No.(μM) 6.5 μg/mL Free fraction Example 1 from 1.50 <0.001 (cryst.) 0.7% WO 2014/022766 Example 100 from 1.33 0.005 (amphor.)  5% WO 2013/022814353 0.50 6 (cryst.)  9% 362 0.37 16 (amphor.) 17% 363 0.34 159 (amphor.)25% 367 0.32 100 (amphor.) 21% 368 0.36 82 (amphor.) 21% 369 0.52 2(cryst.)  8% 370 0.42 106 (amphor.) 24% 371 0.37 44 (cryst.) 26% 3720.22 >3,000 (amphor.) 25% 373 0.24 >3,400 (amphor.) 11%

B. In Vivo Assays

The effectiveness of compounds of the present invention asantithrombotic agents can be determined using relevant in vivothrombosis models, including In Vivo Electrically-induced Carotid ArteryThrombosis Models and In Vivo Rabbit Arteriovenous Shunt ThrombosisModels.

a. In Vivo Electrically-Induced Carotid Artery Thrombosis (ECAT) Model

The rabbit ECAT model, described by Wong et al. (J. Pharmacol. Exp.Ther., 295:212-218 (2000)), can be used in this study. Male New ZealandWhite rabbits are anesthetized with ketamine (50 mg/kg+50 mg/kg/h IM)and xylazine (10 mg/kg+10 mg/kg/h IM). These anesthetics aresupplemented as needed. An electromagnetic flow probe is placed on asegment of an isolated carotid artery to monitor blood flow. Test agentsor vehicle will be given (i.v., i.p., s.c., or orally) prior to or afterthe initiation of thrombosis. Drug treatment prior to initiation ofthrombosis is used to model the ability of test agents to prevent andreduce the risk of thrombus formation, whereas dosing after initiationis used to model the ability to treat existing thrombotic disease.Thrombus formation is induced by electrical stimulation of the carotidartery for 3 min at 4 mA using an external stainless-steel bipolarelectrode. Carotid blood flow is measured continuously over a 90-minperiod to monitor thrombus-induced occlusion. Total carotid blood flowover 90 min is calculated by the trapezoidal rule. Average carotid flowover 90 min is then determined by converting total carotid blood flowover 90 min to percent of total control carotid blood flow, which wouldresult if control blood flow had been maintained continuously for 90min. The ED₅₀ (dose that increased average carotid blood flow over 90min to 50% of the control) of compounds are estimated by a nonlinearleast square regression program using the Hill sigmoid E_(max) equation(DeltaGraph; SPSS Inc., Chicago, Ill.).

b. In Vivo Rabbit Arteriovenous (AV) Shunt Thrombosis Model

The rabbit AV shunt model, described by Wong et al. (Wong, P. C. et al.,J. Pharmacol. Exp. Ther. 292:351-357 (2000)), can be used in this study.Male New Zealand White rabbits are anesthetized with ketamine (50mg/kg+50 mg/kg/h IM) and xylazine (10 mg/kg+10 mg/kg/h IM). Theseanesthetics are supplemented as needed. The femoral artery, jugular veinand femoral vein are isolated and catheterized. A saline-filled AV shuntdevice is connected between the femoral arterial and the femoral venouscannulae. The AV shunt device consists of an outer piece of tygon tubing(length=8 cm; internal diameter=7.9 mm) and an inner piece of tubing(length=2.5 cm; internal diameter=4.8 mm). The AV shunt also contains an8-cm-long 2-0 silk thread (Ethicon, Somerville, N.J.). Blood flows fromthe femoral artery via the AV-shunt into the femoral vein. The exposureof flowing blood to a silk thread induces the formation of a significantthrombus. Forty minutes later, the shunt is disconnected and the silkthread covered with thrombus is weighed. Test agents or vehicle will begiven (i.v., i.p., s.c., or orally) prior to the opening of the AVshunt. The percentage inhibition of thrombus formation is determined foreach treatment group. The ID₅₀ values (dose that produces 50% inhibitionof thrombus formation) are estimated by a nonlinear least squareregression program using the Hill sigmoid E_(max) equation (DeltaGraph;SPSS Inc., Chicago, Ill.).

The anti-inflammatory effect of these compounds can be demonstrated inan Evans Blue dye extravasation assay using C1-esterase inhibitordeficient mice. In this model, mice are dosed with a compound of thepresent invention, Evans Blue dye is injected via the tail vein, andextravasation of the blue dye is determined by spectrophotometric meansfrom tissue extracts.

The ability of the compounds of the current invention to reduce orprevent the systemic inflammatory response syndrome, for example, asobserved during on-pump cardiovascular procedures, can be tested in invitro perfusion systems, or by on-pump surgical procedures in largermammals, including dogs and baboons. Read-outs to assess the benefit ofthe compounds of the present invention include for example reducedplatelet loss, reduced platelet/white blood cell complexes, reducedneutrophil elastase levels in plasma, reduced activation of complementfactors, and reduced activation and/or consumption of contact activationproteins (plasma kallikrein, factor XII, factor XI, high molecularweight kininogen, C1-esterase inhibitors).

The compounds of the present invention may also be useful as inhibitorsof additional serine proteases, notably human thrombin, human plasmakallikrein and human plasmin. Because of their inhibitory action, thesecompounds are indicated for use in the prevention or treatment ofphysiological reactions, including blood coagulation, fibrinolysis,blood pressure regulation and inflammation, and wound healing catalyzedby the aforesaid class of enzymes. Specifically, the compounds haveutility as drugs for the treatment of diseases arising from elevatedthrombin activity of the aforementioned serine proteases, such asmyocardial infarction, and as reagents used as anticoagulants in theprocessing of blood to plasma for diagnostic and other commercialpurposes.

V. Pharmaceutical Compositions, Formulations and Combinations

The compounds of this invention can be administered in such oral dosageforms as tablets, capsules (each of which includes sustained release ortimed release formulations), pills, powders, granules, elixirs,tinctures, suspensions, syrups, and emulsions. They may also beadministered in intravenous (bolus or infusion), intraperitoneal,subcutaneous, or intramuscular form, all using dosage forms well knownto those of ordinary skill in the pharmaceutical arts. They can beadministered alone, but generally will be administered with apharmaceutical carrier selected on the basis of the chosen route ofadministration and standard pharmaceutical practice.

The term “pharmaceutical composition” means a composition comprising acompound of the invention in combination with at least one additionalpharmaceutically acceptable carrier. A “pharmaceutically acceptablecarrier” refers to media generally accepted in the art for the deliveryof biologically active agents to animals, in particular, mammals,including, i.e., adjuvant, excipient or vehicle, such as diluents,preserving agents, fillers, flow regulating agents, disintegratingagents, wetting agents, emulsifying agents, suspending agents,sweetening agents, flavoring agents, perfuming agents, antibacterialagents, antifungal agents, lubricating agents and dispensing agents,depending on the nature of the mode of administration and dosage forms.Pharmaceutically acceptable carriers are formulated according to anumber of factors well within the purview of those of ordinary skill inthe art. These include, without limitation: the type and nature of theactive agent being formulated; the subject to which the agent-containingcomposition is to be administered; the intended route of administrationof the composition; and the therapeutic indication being targeted.Pharmaceutically acceptable carriers include both aqueous andnon-aqueous liquid media, as well as a variety of solid and semi-soliddosage forms. Such carriers can include a number of differentingredients and additives in addition to the active agent, suchadditional ingredients being included in the formulation for a varietyof reasons, e.g., stabilization of the active agent, binders, etc., wellknown to those of ordinary skill in the art. Descriptions of suitablepharmaceutically acceptable carriers, and factors involved in theirselection, are found in a variety of readily available sources such as,for example, Remington's Pharmaceutical Sciences, 18th Edition (1990).

The dosage regimen for the compounds of the present invention will, ofcourse, vary depending upon known factors, such as the pharmacodynamiccharacteristics of the particular agent and its mode and route ofadministration; the species, age, sex, health, medical condition, andweight of the recipient; the nature and extent of the symptoms; the kindof concurrent treatment; the frequency of treatment; the route ofadministration, the renal and hepatic function of the patient, and theeffect desired. A physician or veterinarian can determine and prescribethe effective amount of the drug required to prevent, counter, or arrestthe progress of the thromboembolic disorder.

By way of general guidance, the daily oral dosage of each activeingredient, when used for the indicated effects, will range betweenabout 0.001 to about 1000 mg/kg of body weight, preferably between about0.01 to about 100 mg/kg of body weight per day, and most preferablybetween about 0.1 to about 20 mg/kg/day. Intravenously, the mostpreferred doses will range from about 0.001 to about 10 mg/kg/minuteduring a constant rate infusion. Compounds of this invention may beadministered in a single daily dose, or the total daily dosage may beadministered in divided doses of two, three, or four times daily.

Compounds of this invention can also be administered by parenteraladministration (e.g., intra-venous, intra-arterial, intramuscularly, orsubcutaneously. When administered intra-venous or intra-arterial, thedose can be given continuously or intermittent. Furthermore, formulationcan be developed for intramuscularly and subcutaneous delivery thatensure a gradual release of the active pharmaceutical ingredient. In oneembodiment, the pharmaceutical composition is a solid formulation, e.g.,a spray-dried composition, which may be used as is, or whereto thephysician or the patient adds solvents, and/or diluents prior to use.

Compounds of this invention can be administered in intranasal form viatopical use of suitable intranasal vehicles, or via transdermal routes,using transdermal skin patches. When administered in the form of atransdermal delivery system, the dosage administration will, of course,be continuous rather than intermittent throughout the dosage regimen.

The compounds are typically administered in admixture with suitablepharmaceutical diluents, excipients, or carriers (collectively referredto herein as pharmaceutical carriers) suitably selected with respect tothe intended form of administration, e.g., oral tablets, capsules,elixirs, and syrups, and consistent with conventional pharmaceuticalpractices.

For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic, pharmaceutically acceptable, inert carrier such as lactose,starch, sucrose, glucose, methyl cellulose, magnesium stearate,dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like;for oral administration in liquid form, the oral drug components can becombined with any oral, non-toxic, pharmaceutically acceptable inertcarrier such as ethanol, glycerol, water, and the like. Moreover, whendesired or necessary, suitable binders, lubricants, disintegratingagents, and coloring agents can also be incorporated into the mixture.Suitable binders include starch, gelatin, natural sugars such as glucoseor beta-lactose, corn sweeteners, natural and synthetic gums such asacacia, tragacanth, or sodium alginate, carboxymethylcellulose,polyethylene glycol, waxes, and the like. Lubricants used in thesedosage forms include sodium oleate, sodium stearate, magnesium stearate,sodium benzoate, sodium acetate, sodium chloride, and the like.Disintegrators include, without limitation, starch, methyl cellulose,agar, bentonite, xanthan gum, and the like.

The compounds of the present invention can also be administered in theform of liposome delivery systems, such as small unilamellar vesicles,large unilamellar vesicles, and multilamellar vesicles. Liposomes can beformed from a variety of phospholipids, such as cholesterol,stearylamine, or phosphatidylcholines.

Compounds of the present invention may also be coupled with solublepolymers as targetable drug carriers. Such polymers can includepolyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamidephenol,polyhydroxyethylaspartamidephenol, or polyethyleneoxide-polylysinesubstituted with palmitoyl residues. Furthermore, the compounds of thepresent invention may be coupled to a class of biodegradable polymersuseful in achieving controlled release of a drug, for example,polylactic acid, polyglycolic acid, copolymers of polylactic andpolyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid,polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, andcrosslinked or amphipathic block copolymers of hydrogels. Soliddispersions are also called solid-state dispersions. In someembodiments, any compound described herein is formulated as a spraydried dispersion (SDD). An SDD is a single phase amorphous moleculardispersion of a drug in a polymer matrix. It is a solid solutionprepared by dissolving the drug and a polymer in a solvent (e.g.,acetone, methanol or the like) and spray drying the solution. Thesolvent rapidly evaporates from droplets which rapidly solidifies thepolymer and drug mixture trapping the drug in amorphous form as anamorphous molecular dispersion.

Dosage forms (pharmaceutical compositions) suitable for administrationmay contain from about 1 milligram to about 1000 milligrams of activeingredient per dosage unit. In these pharmaceutical compositions theactive ingredient will ordinarily be present in an amount of about0.1-95% by weight based on the total weight of the composition.

Gelatin capsules may contain the active ingredient and powderedcarriers, such as lactose, starch, cellulose derivatives, magnesiumstearate, stearic acid, and the like. Similar diluents can be used tomake compressed tablets. Both tablets and capsules can be manufacturedas sustained release products to provide for continuous release ofmedication over a period of hours. Compressed tablets can be sugarcoated or film coated to mask any unpleasant taste and protect thetablet from the atmosphere, or enteric coated for selectivedisintegration in the gastrointestinal tract.

Liquid dosage forms for oral administration can contain coloring andflavoring to increase patient acceptance.

In general, water, a suitable oil, saline, aqueous dextrose (glucose),and related sugar solutions and glycols such as propylene glycol orpolyethylene glycols are suitable carriers for parenteral solutions.Solutions for parenteral administration preferably contain a watersoluble salt of the active ingredient, suitable stabilizing agents, andif necessary, buffer substances. Antioxidizing agents such as sodiumbisulfite, sodium sulfite, or ascorbic acid, either alone or combined,are suitable stabilizing agents. Also used are citric acid and its saltsand sodium EDTA. In addition, parenteral solutions can containpreservatives, such as benzalkonium chloride, methyl- or propyl-paraben,and chlorobutanol.

Suitable pharmaceutical carriers are described in Remington'sPharmaceutical Sciences, Mack Publishing Company, a standard referencetext in this field.

Where the compounds of this invention are combined with otheranticoagulant agents, for example, a daily dosage may be about 0.1 toabout 100 milligrams of the compound of the present invention and about0.1 to about 100 milligrams per kilogram of patient body weight. For atablet dosage form, the compounds of this invention generally may bepresent in an amount of about 5 to about 300 milligrams per dosage unit,and the second anti-coagulant in an amount of about 1 to about 500milligrams per dosage unit.

Where the compounds of the present invention are administered incombination with an anti-platelet agent, by way of general guidance,typically a daily dosage may be about 0.01 to about 300 milligrams ofthe compound of the present invention and about 50 to about 150milligrams of the anti-platelet agent, preferably about 0.1 to about 4milligrams of the compound of the present invention and about 1 to about3 milligrams of antiplatelet agents, per kilogram of patient bodyweight.

Where the compounds of the present invention are administered incombination with thrombolytic agent, typically a daily dosage may beabout 0.1 to about 100 milligrams of the compound of the presentinvention, per kilogram of patient body weight and, in the case of thethrombolytic agents, the usual dosage of the thrombolytic agent whenadministered alone may be reduced by about 50-80% when administered witha compound of the present invention.

Particularly when provided as a single dosage unit, the potential existsfor a chemical interaction between the combined active ingredients. Forthis reason, when the compound of the present invention and a secondtherapeutic agent are combined in a single dosage unit they areformulated such that although the active ingredients are combined in asingle dosage unit, the physical contact between the active ingredientsis minimized (that is, reduced). For example, one active ingredient maybe enteric coated. By enteric coating one of the active ingredients, itis possible not only to minimize the contact between the combined activeingredients, but also, it is possible to control the release of one ofthese components in the gastrointestinal tract such that one of thesecomponents is not released in the stomach but rather is released in theintestines. One of the active ingredients may also be coated with amaterial that affects a sustained-release throughout thegastrointestinal tract and also serves to minimize physical contactbetween the combined active ingredients. Furthermore, thesustained-released component can be additionally enteric coated suchthat the release of this component occurs only in the intestine. Stillanother approach would involve the formulation of a combination productin which the one component is coated with a sustained and/or entericrelease polymer, and the other component is also coated with a polymersuch as a low viscosity grade of hydroxypropyl methylcellulose (HPMC) orother appropriate materials as known in the art, in order to furtherseparate the active components. The polymer coating serves to form anadditional barrier to interaction with the other component.

These as well as other ways of minimizing contact between the componentsof combination products of the present invention, whether administeredin a single dosage form or administered in separate forms but at thesame time by the same manner, will be readily apparent to those skilledin the art, once armed with the present disclosure.

In another embodiment, the present invention provides a pharmaceuticalcomposition further comprising additional therapeutic agent(s) selectedfrom potassium channel openers, potassium channel blockers, calciumchannel blockers, sodium hydrogen exchanger inhibitors, antiarrhythmicagents, antiatherosclerotic agents, anticoagulants, antithromboticagents, prothrombolytic agents, fibrinogen antagonists, diuretics,antihypertensive agents, ATPase inhibitors, mineralocorticoid receptorantagonists, phospodiesterase inhibitors, antidiabetic agents,anti-inflammatory agents, antioxidants, angiogenesis modulators,antiosteoporosis agents, hormone replacement therapies, hormone receptormodulators, oral contraceptives, antiobesity agents, antidepressants,antianxiety agents, antipsychotic agents, antiproliferative agents,antitumor agents, antiulcer and gastroesophageal reflux disease agents,growth hormone agents and/or growth hormone secretagogues, thyroidmimetics, anti-infective agents, antiviral agents, antibacterial agents,antifungal agents, cholesterol/lipid lowering agents and lipid profiletherapies, and agents that mimic ischemic preconditioning and/ormyocardial stunning, or a combination thereof.

In another embodiment, the present invention provides a pharmaceuticalcomposition further comprising additional therapeutic agent(s) selectedfrom an anti-arrhythmic agent, an anti-hypertensive agent, ananti-coagulant agent, an anti-platelet agent, a thrombin inhibitingagent, a thrombolytic agent, a fibrinolytic agent, a calcium channelblocker, a potassium channel blocker, a cholesterol/lipid loweringagent, or a combination thereof.

In another embodiment, the present invention provides a pharmaceuticalcomposition further comprising additional therapeutic agent(s) selectedfrom warfarin, unfractionated heparin, low molecular weight heparin,synthetic pentasaccharide, hirudin, argatroban, aspirin, ibuprofen,naproxen, sulindac, indomethacin, mefenamate, dipyridamol, droxicam,diclofenac, sulfinpyrazone, piroxicam, ticlopidine, clopidogrel,tirofiban, eptifibatide, abciximab, melagatran, ximelagatran,disulfatohirudin, tissue plasminogen activator, modified tissueplasminogen activator, anistreplase, urokinase, and streptokinase, or acombination thereof.

In another embodiment, the present invention provides a pharmaceuticalcomposition wherein the additional therapeutic agent is anantihypertensive agent selected from ACE inhibitors, AT-1 receptorantagonists, beta-adrenergic receptor antagonists, ETA receptorantagonists, dual ETA/AT-1 receptor antagonists, renin inhibitors(aliskiren) and vasopepsidase inhibitors, an antiarrythmic agentselected from I_(Kur) inhibitors, an anticoagulant selected fromthrombin inhibitors, antithrombin-III activators, heparin co-factor IIactivators, other factor XIa inhibitors, other kallikrein inhibitors,plasminogen activator inhibitor (PAI-1) antagonists, thrombinactivatable fibrinolysis inhibitor (TAFI) inhibitors, factor VIIainhibitors, factor IXa inhibitors, and factor Xa inhibitors, or anantiplatelet agent selected from GPIIb/IIIa blockers, GP Ib/IX blockers,protease activated receptor 1 (PAR-1) antagonists, protease activatedreceptor4 (PAR-4) antagonists, prostaglandin E2 receptor EP3antagonists, collagen receptor antagonists, phosphodiesterase-IIIinhibitors, P2Y₁ receptor antagonists, P2Y₁₂ antagonists, thromboxanereceptor antagonists, cyclooxygense-1 inhibitors, and aspirin, or acombination thereof.

In another embodiment, the present invention provides pharmaceuticalcomposition, wherein the additional therapeutic agent(s) are ananti-platelet agent or a combination thereof.

In another embodiment, the present invention provides a pharmaceuticalcomposition, wherein the additional therapeutic agent is theanti-platelet agent clopidogrel.

The compounds of the present invention can be administered alone or incombination with one or more additional therapeutic agents. By“administered in combination” or “combination therapy” it is meant thatthe compound of the present invention and one or more additionaltherapeutic agents are administered concurrently to the mammal beingtreated. When administered in combination, each component may beadministered at the same time or sequentially in any order at differentpoints in time. Thus, each component may be administered separately butsufficiently closely in time so as to provide the desired therapeuticeffect.

Compounds that can be administered in combination with the compounds ofthe present invention include, but are not limited to, anticoagulants,anti-thrombin agents, anti-platelet agents, fibrinolytics, hypolipidemicagents, antihypertensive agents, and anti-ischemic agents.

Other anticoagulant agents (or coagulation inhibitory agents) that maybe used in combination with the compounds of this invention includewarfarin, heparin (either unfractionated heparin or any commerciallyavailable low molecular weight heparin, for example LOVENOX®), syntheticpentasaccharide, direct acting thrombin inhibitors including hirudin andargatroban, as well as other factor VIIa inhibitors, factor IXainhibitors, factor Xa inhibitors (e.g., ARIXTRA®, apixaban, rivaroxaban,LY-517717, DU-176b, DX-9065a, and those disclosed in WO 98/57951, WO03/026652, WO 01/047919, and WO 00/076970), factor XIa inhibitors, andinhibitors of activated TAFI and PAI-1 known in the art.

The term anti-platelet agents (or platelet inhibitory agents), as usedherein, denotes agents that inhibit platelet function, for example, byinhibiting the aggregation, adhesion or granule-content secretion ofplatelets. Such agents include, but are not limited to, the variousknown non-steroidal anti-inflammatory drugs (NSAIDs) such asacetaminophen, aspirin, codeine, diclofenac, droxicam, fentaynl,ibuprofen, indomethacin, ketorolac, mefenamate, morphine, naproxen,phenacetin, piroxicam, sufentanyl, sulfinpyrazone, sulindac, andpharmaceutically acceptable salts or prodrugs thereof. Of the NSAIDs,aspirin (acetylsalicylic acid or ASA) and piroxicam are preferred. Othersuitable platelet inhibitory agents include glycoprotein IIb/IIIaantagonists (e.g., tirofiban, eptifibatide, abciximab, and integrelin),thromboxane-A2-receptor antagonists (e.g., ifetroban),thromboxane-A-synthetase inhibitors, phosphodiesterase-III (PDE-III)inhibitors (e.g., dipyridamole, cilostazol), and PDE-V inhibitors (suchas sildenafil), protease-activated receptor 1 (PAR-1) antagonists (e.g.,E-5555, SCH-530348, SCH-203099, SCH-529153 and SCH-205831), andpharmaceutically acceptable salts or prodrugs thereof.

Other examples of suitable anti-platelet agents for use in combinationwith the compounds of the present invention, with or without aspirin,are ADP (adenosine diphosphate) receptor antagonists, preferablyantagonists of the purinergic receptors P2Y₁ and P2Y₁₂, with P2Y₁₂ beingeven more preferred. Preferred P2Y₁₂ receptor antagonists includeclopidogrel, ticlopidine, prasugrel, ticagrelor, and cangrelor, andpharmaceutically acceptable salts or prodrugs thereof. Ticlopidine andclopidogrel are also preferred compounds since they are known to be moregentle than aspirin on the gastrointestinal tract in use. Clopidogrel isan even more preferred agent.

A preferred example is a triple combination of a compound of the presentinvention, aspirin, and another anti-platelet agent. Preferably, theanti-platelet agent is clopidogrel or prasugrel, more preferablyclopidogrel.

The term thrombin inhibitors (or anti-thrombin agents), as used herein,denotes inhibitors of the serine protease thrombin. By inhibitingthrombin, various thrombin-mediated processes, such as thrombin-mediatedplatelet activation (that is, for example, the aggregation of platelets,and/or the secretion of platelet granule contents including serotonin)and/or fibrin formation are disrupted. A number of thrombin inhibitorsare known to one of skill in the art and these inhibitors arecontemplated to be used in combination with the present compounds. Suchinhibitors include, but are not limited to, boroarginine derivatives,boropeptides, heparins, hirudin, argatroban, dabigatran, AZD-0837, andthose disclosed in WO 98/37075 and WO 02/044145, and pharmaceuticallyacceptable salts and prodrugs thereof. Boroarginine derivatives andboropeptides include N-acetyl and peptide derivatives of boronic acid,such as C-terminal a-aminoboronic acid derivatives of lysine, omithine,arginine, homoarginine and corresponding isothiouronium analogs thereof.The term hirudin, as used herein, includes suitable derivatives oranalogs of hirudin, referred to herein as hirulogs, such asdisulfatohirudin.

The term thrombolytic (or fibrinolytic) agents (or thrombolytics orfibrinolytics), as used herein, denotes agents that lyse blood clots(thrombi). Such agents include tissue plasminogen activator (TPA,natural or recombinant) and modified forms thereof, anistreplase,urokinase, streptokinase, tenecteplase (TNK), lanoteplase (nPA), factorVIIa inhibitors, thrombin inhibitors, inhibitors of factors IXa, Xa, andXIa, PAI-I inhibitors (i.e., inactivators of tissue plasminogenactivator inhibitors), inhibitors of activated TAFI, alpha-2-antiplasmininhibitors, and anisoylated plasminogen streptokinase activator complex,including pharmaceutically acceptable salts or prodrugs thereof. Theterm anistreplase, as used herein, refers to anisoylated plasminogenstreptokinase activator complex, as described, for example, in EuropeanPatent Application No. 028,489, the disclosure of which is herebyincorporated herein by reference herein. The term urokinase, as usedherein, is intended to denote both dual and single chain urokinase, thelatter also being referred to herein as prourokinase.

Examples of suitable cholesterol/lipid lowering agents and lipid profiletherapies for use in combination with the compounds of the presentinvention include HMG-CoA reductase inhibitors (e.g., pravastatin,lovastatin, simvastatin, fluvastatin, atorvastatin, rosuvastatin, andother statins), low-density lipoprotein (LDL) receptor activitymodulators (e.g., HOE-402, PCSK9 inhibitors), bile acid sequestrants(e.g., cholestyramine and colestipol), nicotinic acid or derivativesthereof (e.g., NIASPAN®), GPR109B (nicotinic acid receptor) modulators,fenofibric acid derivatives (e.g., gemfibrozil, clofibrate, fenofibrateand benzafibrate) and other peroxisome proliferator-activated receptors(PPAR) alpha modulators, PPARdelta modulators (e.g., GW-501516),PPARgamma modulators (e.g., rosiglitazone), compounds that have multiplefunctionality for modulating the activities of various combinations ofPPARalpha, PPARgamma and PPARdelta, probucol or derivatives thereof(e.g., AGI-1067), cholesterol absorption inhibitors and/or Niemann-PickC1-like transporter inhibitors (e.g., ezetimibe), cholesterol estertransfer protein inhibitors (e.g., CP-529414), squalene synthaseinhibitors and/or squalene epoxidase inhibitors or mixtures thereof,acyl coenzyme A: cholesteryl acyltransferase (ACAT) 1 inhibitors, ACAT2inhibitors, dual ACAT1/2 inhibitors, ileal bile acid transportinhibitors (or apical sodium co-dependent bile acid transportinhibitors), microsomal triglyceride transfer protein inhibitors,liver-X-receptor (LXR) alpha modulators, LXRbeta modulators, LXR dualalpha/beta modulators, FXR modulators, omega 3 fatty acids (e.g.,3-PUFA), plant stanols and/or fatty acid esters of plant stanols (e.g.,sitostanol ester used in BENECOL® margarine), endothelial lipaseinhibitors, and HDL functional mimetics which activate reversecholesterol transport (e.g., apoAI derivatives or apoAI peptidemimetics).

The compounds of the present invention can also be combined with solubleguanylate cyclase inhibitors, Chymase inhibitors, ROMK inhibitors, ACEinhibitors, ATII inhibitors, ATR inhibitors, NEP inhibitors and othercompounds to treat heart failure.

The compounds of the present invention are also useful as standard orreference compounds, for example as a quality standard or control, intests or assays involving the inhibition of thrombin, Factor VIIa, IXa,Xa, XIa, and/or plasma kallikrein. Such compounds may be provided in acommercial kit, for example, for use in pharmaceutical researchinvolving thrombin, Factor VIIa, IXa, Xa, XIa, and/or plasma kallikrein.XIa. For example, a compound of the present invention could be used as areference in an assay to compare its known activity to a compound withan unknown activity. This would ensure the experimentor that the assaywas being performed properly and provide a basis for comparison,especially if the test compound was a derivative of the referencecompound. When developing new assays or protocols, compounds accordingto the present invention could be used to test their effectiveness.

The compounds of the present invention may also be used in diagnosticassays involving thrombin, Factor VIIa, IXa, Xa, XIa, and/or plasmakallikrein. For example, the presence of thrombin, Factor VIIa, IXa, XaXIa, and/or plasma kallikrein in an unknown sample could be determinedby addition of the relevant chromogenic substrate, for example S2366 forFactor XIa, to a series of solutions containing test sample andoptionally one of the compounds of the present invention. If productionof pNA is observed in the solutions containing test sample, but not inthe presence of a compound of the present invention, then one wouldconclude Factor XIa was present.

Extremely potent and selective compounds of the present invention, thosehaving K_(i) values less than or equal to 0.001 μM against the targetprotease and greater than or equal to 0.1 μM against the otherproteases, may also be used in diagnostic assays involving thequantitation of thrombin, Factor VIIa, IXa, Xa, XIa, and/or plasmakallikrein in serum samples. For example, the amount of Factor XIa inserum samples could be determined by careful titration of proteaseactivity in the presence of the relevant chromogenic substrate, S2366,with a potent Factor XIa inhibitor of the present invention.

The present invention also encompasses an article of manufacture. Asused herein, article of manufacture is intended to include, but not belimited to, kits and packages. The article of manufacture of the presentinvention, comprises: (a) a first container; (b) a pharmaceuticalcomposition located within the first container, wherein the composition,comprises: a first therapeutic agent, comprising: a compound of thepresent invention or a pharmaceutically acceptable salt form thereof;and, (c) a package insert stating that the pharmaceutical compositioncan be used for the treatment of a thromboembolic and/or inflammatorydisorder (as defined previously). In another embodiment, the packageinsert states that the pharmaceutical composition can be used incombination (as defined previously) with a second therapeutic agent totreat a thromboembolic and/or inflammatory disorder. The article ofmanufacture can further comprise: (d) a second container, whereincomponents (a) and (b) are located within the second container andcomponent (c) is located within or outside of the second container.Located within the first and second containers means that the respectivecontainer holds the item within its boundaries.

The first container is a receptacle used to hold a pharmaceuticalcomposition. This container can be for manufacturing, storing, shipping,and/or individual/bulk selling. First container is intended to cover abottle, jar, vial, flask, syringe, tube (e.g., for a cream preparation),or any other container used to manufacture, hold, store, or distribute apharmaceutical product.

The second container is one used to hold the first container and,optionally, the package insert. Examples of the second containerinclude, but are not limited to, boxes (e.g., cardboard or plastic),crates, cartons, bags (e.g., paper or plastic bags), pouches, and sacks.The package insert can be physically attached to the outside of thefirst container via tape, glue, staple, or another method of attachment,or it can rest inside the second container without any physical means ofattachment to the first container. Alternatively, the package insert islocated on the outside of the second container. When located on theoutside of the second container, it is preferable that the packageinsert is physically attached via tape, glue, staple, or another methodof attachment. Alternatively, it can be adjacent to or touching theoutside of the second container without being physically attached.

The package insert is a label, tag, marker, etc. that recitesinformation relating to the pharmaceutical composition located withinthe first container. The information recited will usually be determinedby the regulatory agency governing the area in which the article ofmanufacture is to be sold (e.g., the United States Food and DrugAdministration). Preferably, the package insert specifically recites theindications for which the pharmaceutical composition has been approved.The package insert may be made of any material on which a person canread information contained therein or thereon. Preferably, the packageinsert is a printable material (e.g., paper, plastic, cardboard, foil,adhesive-backed paper or plastic, etc.) on which the desired informationhas been formed (e.g., printed or applied).

Other features of the invention will become apparent in the course ofthe following descriptions of exemplary embodiments that are given forillustration of the invention and are not intended to be limitingthereof. The following Examples have been prepared, isolated andcharacterized using the methods disclosed herein.

VI. General Synthesis Including Schemes

The compounds of the present invention may be synthesized by manymethods available to those skilled in the art of organic chemistry(Maffrand, J. P. et al., Heterocycles, 16(1):35-37 (1981)). Generalsynthetic schemes for preparing compounds of the present invention aredescribed below. These schemes are illustrative and are not meant tolimit the possible techniques one skilled in the art may use to preparethe compounds disclosed herein. Different methods to prepare thecompounds of the present invention will be evident to those skilled inthe art. Additionally, the various steps in the synthesis may beperformed in an alternate sequence in order to give the desired compoundor compounds.

Examples of compounds of the present invention prepared by methodsdescribed in the general schemes are given in the intermediates andexamples section set out hereinafter. Preparation of homochiral examplesmay be carried out by techniques known to one skilled in the art. Forexample, homochiral compounds may be prepared by separation of racemicproducts by chiral phase preparative HPLC. Alternatively, the examplecompounds may be prepared by methods known to give enantiomericallyenriched products. These include, but are not limited to, theincorporation of chiral auxiliary functionalities into racemicintermediates which serve to control the diastereoselectivity oftransformations, providing enantio-enriched products upon cleavage ofthe chiral auxiliary.

The compounds of the present invention can be prepared in a number ofways known to one skilled in the art of organic synthesis. The compoundsof the present invention can be synthesized using the methods describedbelow, together with synthetic methods known in the art of syntheticorganic chemistry, or by variations thereon as appreciated by thoseskilled in the art. Preferred methods include, but are not limited to,those described below. The reactions are performed in a solvent orsolvent mixture appropriate to the reagents and materials employed andsuitable for the transformations being effected. It will be understoodby those skilled in the art of organic synthesis that the functionalitypresent on the molecule should be consistent with the transformationsproposed. This will sometimes require a judgment to modify the order ofthe synthetic steps or to select one particular process scheme overanother in order to obtain a desired compound of the invention.

It will also be recognized that another major consideration in theplanning of any synthetic route in this field is the judicious choice ofthe protecting group used for protection of the reactive functionalgroups present in the compounds described in this invention. Anauthoritative account describing the many alternatives to the trainedpractitioner is Greene et al. (Protective Groups in Organic Synthesis,Fourth Edition, Wiley-Interscience (2006)).

Representative pyrimidinone compounds 1a of this invention can beprepared as described in Scheme 1. Using a modified procedure describedby Xiao (Organic Letters, 11:1421 (2009)), suitably substitutedpyrimidin-4-ol derivatives 1b can be coupled with an appropriatelysubstituted macrocycle amine 1c in the presence of HATU and DBU in asolvent such as CH₃CN to provide pyrimidinone compounds 1a. When ring Ais a SEM-protected imidazole ring, an additional deprotection stepemploying 4N HCl in dioxane or TFA in DCM is used to afford compounds ofthis invention.

Scheme 2 describes the synthesis of suitably substituted pyrimidin-4-olderivatives 1b. Suzuki-Miyaura coupling between 6-chloropyrimidin-4-ol(2a) and an appropriately substituted heteroaryl boronic acid or ester2c in the presence of a base such as Hunig's base or potassium phosphatetribasic, in a solvent mixture, such as toluene and ethanol, or THF,using a precatalyst such as Pd(PPh₃)₄ or 2nd generation XPhos provides1b. Alternatively, when 4-chloro-6-methoxypyrimidine 2b is used, anadditional deprotection step, employing aqueous HBr at elevatedtemperatures, is required to provide pyrimidin-4-ol derivatives 1b.

Intermediates for preparation of compounds of the present inventionwherein ring A and B are a 6-membered heterocyclyl (example—pyridine)can be derived from appropriately substituted aldehydes 3a according tothe general method outlined in Scheme 3. Condensation of aldehyde 3a(X═N, Y═Z=M=CH) prepared according to a modified procedure described byNegi (Synthesis, 991 (1996)), with (S)-2-methylpropane-2-sulfinamide inthe presence of anhydrous copper sulfate or cesium carbonate in asolvent such as DCM gives the sulfinimine 3b (Ellman, J., J. Org. Chem.,64:1278 (1999)). Using a modified procedure described by Kuduk(Tetrahedron Letters, 45:6641 (2004)), suitably substituted Grignardreagents, for example allylmagnesium bromide, can be added tosulfinimine 3b to give a sulfinamide 3c, as a mixture of diastereomerswhich can be separated at various stages of the sequence. Thediastereoselectivity for the addition of allylmagnesium bromide tosulfinimine 3b can be improved by employing indium(III) chlorideaccording to a modified procedure of Xu (Xu, M-H, Organic Letters,10(6):1259 (2008)). Suzuki-Miyaura coupling between 4-chloropyridine 3cand an appropriately substituted heteroaryl boronic acid or ester 3e inthe presence of a base such as potassium phosphate, in a solventmixture, such as DMSO and H₂O, or DMF, using a precatalyst such asPd(dppf)Cl₂.CH₂Cl₂ complex provides 3g. Alternatively, theSuzuki-Miyaura coupling between boronic acid 3d and an appropriatelysubstituted heteroaryl halide 3f can be used to prepare 3g. Protectinggroup interconversion can be accomplished in two steps to give 3h.Alternatively, the protecting group interconversion can take placeinitially on 3c followed by the Suzuki-Miyaura coupling. The aniline 3hcan then be coupled with an appropriately substituted carboxylic acid 3iusing T3P® and a base, such as pyridine, to give the amide 3j. Using amodified procedure described by Lovely (Tetrahedron Letters, 44:1379(2003)), 3j, following pretreatment with p-toluenesulfonic acid to formthe pyridinium ion, can be cyclized via ring-closing metathesis using acatalyst, such as Second Generation Grubbs Catalyst in a suitablesolvent, such as DCM, DCE, or toluene at elevated temperature, to givethe pyridine-containing macrocycle 3k. The alkene can be reduced withhydrogen over either palladium on carbon or platinum oxide, andsubsequent deprotection with TFA in DCM or 4M HCl in dioxane providesamine 3l. Compounds of the formula 3l can be converted to compounds inthis invention according to Scheme 1.

Methods for synthesis of a large variety of substituted pyridinecompounds useful as starting materials for the preparation of compoundsof the present invention are well known in the art and have beenextensively reviewed. (For examples of methods useful for thepreparation of pyridine starting materials see: Kroehnke, F., Synthesis,1 (1976); Abramovitch, R. A., ed., “Pyridine and Its Derivatives”, TheChemistry of Heterocyclic Compounds, 14(Suppl. 1-4), John Wiley & Sons,New York (1974); Boulton, A. J. et al., eds., Comprehensive HeterocyclicChemistry, 2:165-524, Pergamon Press, New York (1984); McKillop, A.,ed., Comprehensive Heterocyclic Chemistry, 5:1-300, Pergamon Press, NewYork (1996)).

In cases where suitably substituted boronic acids are not commerciallyavailable, a modification to this approach may be adopted wherein aheteroaryl halide is subjected to a palladium mediated coupling with adiboron species such as bis(pinacolato) diboron or bis(neopentylglycolato)diboron to provide the corresponding4,4,5,5-tetramethyl-[1,3,2]dioxaborolane or the5,5-dimethyl-[1,3,2]dioxaborolane intermediates using the method ofIshiyama, T. et al. (J. Org. Chem., 60(23):7508-7510 (1995)).Alternately, this same intermediate can be prepared by reaction of theintermediate halide with the corresponding dialkoxyhydroborane asdescribed by Murata et al. (J. Org. Chem., 62(19):6458-6459 (1997)). Theboron pinacolate intermediates can be used in place of boronic acids forcoupling to the aryl/heteroaryl halides or triflates or the boronpinacolate intermediate can be converted to the boronic acids.Alternately, the corresponding boronic acids can be prepared bymetal-halogen exchange of the aryl/heteroaryl halide, quenching with atrialkoxyborate reagent, and aqueous workup to provide the boronic acids(Miyaura, N. et al., Chem. Rev., 95:2457 (1995)).

It is also realized that the scope of intermediate synthesis can befurther extended outside the use of Suzuki-Miyaura coupling methodologysince the precursor heteroaryl halides or triflates described above arealso precursors for Stille, Negishi, Hiyama, and Kumada-type crosscoupling methodologies (Tsuji, J., Transition Metal Reagents andCatalysts: Innovations in Organic Synthesis, John Wiley & Sons (2000);Tsuji, J., Palladium Reagents and Catalysts: Innovations in OrganicSynthesis, John Wiley & Sons (1996)).

Intermediates for preparation of compounds of the present inventionwherein ring A is an imidazole ring, can be prepared from anappropriately N-protected allylglycine (4a) according to the generalmethod outlined in Scheme 4 (Contour-Galcera et al., Bioorg. Med. Chem.Lett., 11(5):741-745 (2001)). Condensation of 4a with a suitablysubstituted alpha-bromo-ketone bearing a heteroaryl group (4b) in thepresence of a suitable base such as potassium bicarbonate, potassiumcarbonate or cesium carbonate in a suitable solvent such as DMF providesa keto ester intermediate which can be cyclized to afford an imidazole(4c) by heating in the presence of excess ammonium acetate in a solventsuch as toluene or xylene. This latter transformation can beconveniently carried out on small scale at 160° C. in a microwavereactor or on larger scale by refluxing the mixture while removing watervia a Dean-Stark trap. The resulting imidazole intermediate (4c) is thenprotected by treatment with SEM-Cl in the presence of a base such assodium hydride or dicyclohexylmethylamine in a solvent such as THF orDCM. The resulting heteroaryl bromide (4d) is then converted to thecorresponding amino-heterocyclyl (4e) by heating in a sealed vessel withexcess ammonium hydroxide, in the presence of copper iodide, a base suchas potassium carbonate and a catalytic amount of proline in DMSO assolvent. Acylation of 4e with the appropriate alkenoic acid and acoupling agent such as T3P® or BOP reagent, or alternately, by treatmentwith an alkenoic acid chloride in the presence of a base such as TEA,DIPEA, or pyridine provides diene 4f, which undergoes ring closingmetathesis by heating in dilute solution in the presence of p-toluenesulfonic acid and Second Generation Grubbs Catalyst in a suitablesolvent such as DCM or DCE to provide the corresponding macrocycle (4g).Alternately, the RCM can be run in a microwave at elevated temperatureswithout pTsOH. Reduction of the double bond followed by bromination withNBS at room temperature affords 4h. Suzuki-Miyaura coupling withmethylboronic acid or tetramethylstannane and removal of the protectinggroup (PG), provides intermediate 4i. Intermediate 4i can be convertedto compounds of the present invention following the steps described inScheme 1.

Scheme 5 describes the intermediates in the present invention where ringB is a heterocyclyl (example—pyrazole). Chloropyridine 3b undergoesprotecting group interconversion to provide 5a which can be coupled to4-nitropyrazoles 5b upon heating with a Pd(II) salt such as Pd(OAc)₂ inthe presence of a phosphine ligand and a base such as potassiumcarbonate in a solvent such as DMF or DMA, as described by Sames(Goikhman, R., Jacques, T. L. and Sames, D., J. Am. Chem. Soc., 131:3042(2009)). Zinc/HOAc reduction of the nitropyrazole, 5c, followed byamidation with an appropriately substituted carboxylic acid, 5d,provides 5e. Macrocyclization is then accomplished via ring-closingmetathesis using the Grubb's second generation ruthenium catalyst toyield 5f. Hydrogenation of the resulting olefin and protecting groupcleavage yields amine 5g. Compounds of the formulae 5g can be convertedto compounds in this invention upon coupling with an appropriatelysubstituted pyrimidin-4-ol derivative, 1b, according to Scheme 1.

Compounds in this invention bearing alternate regiochemical pyrazolesubstitution can be synthesized as shown in Scheme 6. When R is anappropriate protective group (example—trimethylsilylethoxymethyl),deprotection of 6a to 6b can be followed by alkylation with an alkylhalide under basic conditions, upon reaction with a boronic acid in thepresence of Cu(II) salts such as Cu(OAc)₂, or upon reaction with an aryliodide in the presence of CuI and a diamine ligand. In most cases, thealkylation proceeds to give solely the product shown in 6c. In selectcases, products with the pyrazole regiochemistry shown in Scheme 5 areformed as a minor component.

Compounds in this invention bearing alternate regiochemical pyrazolesubstitution can be synthesized as shown in Scheme 6. When R is anappropriate protective group (example—trimethylsilylethoxymethyl),deprotection of 6a to 6b can be followed by alkylation with an alkylhalide under basic conditions, upon reaction with a boronic acid in thepresence of Cu(II) salts such as Cu(OAc)₂, or upon reaction with an aryliodide in the presence of CuI and a diamine ligand. In most cases, thealkylation proceeds to give solely the product shown in 6c. In selectcases, products with the pyrazole regiochemistry shown in Scheme 5 areformed as a minor component.

Intermediates for preparation of compounds of the present inventionwherein R^(1a) is —F can be prepared according to Scheme 7. Olefin 5fcan be subjected to hydrofluorination, yielding as many as four isomericalkyl fluorides. Following separation of the isomers, deprotection ofthe amine protecting group is accomplished by the action of either TFAor HCl, as previously shown in Schemes 3-5. The intermediate 7a and 7bcan be elaborated to compounds of this invention according to theprocedure described in Scheme 1.

Intermediates for preparation of compounds of the present inventioncorresponding to Formula V can be prepared according to Scheme 8.Chloropyridine 5a is reacted with aqueous hydrazine to generatesubstituted hydrazine 8a. This hydrazine can be cyclized upon treatmentwith α-cyanoketones 8b to yield aminopyrazoles 8c. These intermediates(8c) can be elaborated to compounds of this invention according to theprocedures described in Schemes 1 and 3.

Scheme 9 describes the synthesis of suitably substituted pyrimidin-4-olderivatives where G¹ is a substituted phenyl. Aniline 9a can beconverted to a suitably substituted triazole 9b in a one pot, two stepsequence. Specifically, the aniline 9a is converted to the aryl azide insitu followed by cycloaddition with a suitably substituted alkyne in thepresence of a copper catalyst, such as Cu₂O, to provide 9b.Demethylation of 9b according to Scheme 2 provides the pyrimidin-4-olderivatives 9c. When R¹⁰ is a trimethylsilyl group, the silyl moiety canbe converted to a chloride at elevated temperature with NCS in thepresence of silica gel. Aniline 9a can be converted to the iodide 9dwith p-TsOH, NaNO₂, and NaI. Subjecting iodide 9d to a variety ofN-arylation or Suzuki-Miyaura couplings, followed by demethylationaccording to Scheme 2, gives additional pyrimidin-4-ol derivatives 9e.When R⁸ is tetrazole, intermediate 9g can be prepared by first treatmentof the aniline 9a with trimethoxymethane and sodium azide followed bydemethylation according to Scheme 2.

Scheme 10 describes the synthesis of suitably substituted pyrimidin-4-olderivatives where R⁸ is a thiadiazole. Bromide 10a can be converted toacetyl compound 10b by coupling with 1-(trimethylsilyl)ethanone with Pdcatalyst. 10b can react with ethyl hydrazinecarboxylate to form 10c,which upon treatment with SOCl₂ to give thiadiazole compound 10d.Intermediate 10e can be obtained by demethylation of 10d according toScheme 2.

Representative synthesis of compounds in this invention where ring A ismethoxypyridine is outlined in Scheme 11. Benzaldehyde 11a which wasused in a Homer-Wadsworth-Emmons reaction with (S)-tert-butyl(1-(dimethoxyphosphoryl)-2-oxohex-5-en-3-yl)carbamate (synthesispreviously described) to afford 11b. Then, enone 11b was converted intokey intermediate 11c by treatment with NH₄OAc and separated by chiralchromatography to 11d1 and 11d2. Methylation of chiral separationproduct 11d2 gave 2-methyoxy pyridine 11e. Zn mediated reduction ofnitro group afforded aniline 11f. Coupling of aniline 11f with the2-methylbut-3-enoic acid by methods known in the art of synthesisresulted in formation of 11g. The following ring closing metathesisformed two isomers 11h1 and 11h2. Hydrogenation and deprotection of 11h1and 11h2 gave the crucial intermediate 1111 and 1112 which can becoupled to afford compounds of this invention.

The corresponding pyridone compounds of this invention can also beprepared by the methodologies outlined in Schemes 12 to 14.

Other azole containing compounds of this invention can also be accessedvia the schematic shown in Scheme 15 by following the procedure outlinedfor the pyridine/one ring systems.

Alternatively, Examples 353-373 of the present invention can also bemade by the following schemes.

Representative pyrimidinone compounds 1a of this invention can beprepared as described in Scheme 1A. Using a modified procedure describedby Xiao (Org. Lett., 11:1421 (2009)), suitably substitutedpyrimidin-4-ol derivatives 1b can be coupled with an appropriatelysubstituted macrocycle amine 1c in the presence of HATU and DBU in asolvent such as CH₃CN to provide pyrimidinone compounds 1a. When ring Ais a SEM-protected imidazole ring, an additional deprotection stepemploying 4M HCl in dioxane or TFA in DCM is required to affordcompounds of this invention.

Scheme 2A describes the synthesis of suitably substituted pyrimidin-4-olderivatives 1b. Suzuki-Miyaura coupling between 6-chloropyrimidin-4-ol(2a) and an appropriately substituted aryl or heteroaryl boronic acid orester 2c in the presence of a base such as Hunig's base or potassiumphosphate tribasic, in a solvent mixture, such as toluene and ethanol,or THF, using a precatalyst such as Pd(PPh₃)₄ or 2^(nd) generation XPhosprovides 1b. Alternatively, when 4-chloro-6-methoxypyrimidine 2b isused, an additional deprotection step, employing aqueous HBr at elevatedtemperatures, is required to provide pyrimidin-4-ol derivatives 1b.

Intermediates for preparation of compounds of the present inventionwherein ring A is a 6-membered heterocycle (example—pyridine) can bederived from appropriately substituted aldehydes 3a according to thegeneral method outlined in Scheme 3A. Condensation of aldehyde 3a (X═N)prepared according to a modified procedure described by Negi (Synthesis,991 (1996)), with (S)-2-methylpropane-2-sulfinamide in the presence ofanhydrous copper sulfate or cesium carbonate in a solvent such as DCMgives the sulfinimine 3b (Ellman, J., J. Org. Chem., 64:1278 (1999)).Using a modified procedure described by Kuduk (Tetrahedron Letters,45:6641 (2004)), suitably substituted Grignard reagents, for example,allylmagnesium bromide, can be added to sulfinimine 3b to give asulfinamide 3c, as a mixture of diastereomers which can be separated atvarious stages of the sequence. The diastereoselectivity for theaddition of ally magnesium bromide to sulfinimine 3b can be improved byemploying indium(III) chloride according to a modified procedure of Xu(Xu, M.-H., Org. Lett., 10(6): 1259 (2008)). Protecting groupinterconversion can be accomplished in two steps to give 3d. Thecritical subunit coupling is accomplished via methodology developed bySames (J. Am. Chem. Soc., 131:3042 (2009)). Treatment of chloropyridine3d with N-protected nitropyrazole 3e in the presence of catalyticPd(OAc)₂ and P(nBu)Ad₂ forges the desired arylpyrazole bond, forming 3f.Reduction of this nitropyrazole yields 3g. This aminopyrazole can thenbe coupled with an appropriately substituted carboxylic acid 3h usingT3P® and a base, such as pyridine, to give the amide 3i. The diene canbe cyclized via ring-closing metathesis using a catalyst, such as Grubbs(II), in a suitable solvent, such as EtOAc at elevated temperature, togive the pyridine-containing macrocycle 3j. The alkene can be reducedwith hydrogen over either palladium on carbon or platinum oxide. Thesecond coupling reaction is then carried out as described in Scheme 1with pyrimidinol 3k to yield pyrimidinone 3l. Subsequent deprotection ofthe pyrazole with TFA in DCM or 4M HCl in dioxane provides followed byUllmann coupling with an aryl iodide affords 3m as a major regioisomer.If 3n is formed, it is the minor component of the product mixture.

Compounds like 3n can be obtained as exclusive products following thesynthetic 5 procedures in Scheme 4A. All operations are analogous tothose in Scheme 3 up until the pyrazole coupling reaction. Appropriatelysubstituted nitropyrazoles 4a yield the shown regioisomeric pyrazoles 4bunder the same conditions described in Scheme 3. Reduction to 4c,amidation with 3h to form 4d, and ring-closing metathesis to formmacrocycle 4e occur in a similar fashion as well. Reduction of theolefin and deprotection are followed by pyrimidinol coupling, asdescribed in Schemes 1A and 3A.

Purification of intermediates and final products was carried out viaeither normal or reverse phase chromatography. Normal phasechromatography was carried out using pre-packed SiO₂ cartridges elutingwith either gradients of hexanes and EtOAc or DCM and MeOH unlessotherwise indicated. Reverse phase preparative HPLC was carried outusing C18 columns eluting with gradients of Solvent A (90% water, 10%MeOH, 0.1% TFA) and Solvent B (10% water, 90% MeOH, 0.1% TFA, UV 220 nm)or with gradients of Solvent A (90% water, 10% ACN, 0.1% TFA) andSolvent B (10% water, 90% ACN, 0.1% TFA, UV 220 nm) or with gradients ofSolvent A (98% water, 2% ACN, 0.05% TFA) and Solvent B (98% ACN, 2%water, 0.05% TFA, UV 220 nm) (or) SunFire Prep C18 OBD 5μ 30×100 mm, 25min gradient from 0-100% B. A=H₂O/ACN/TFA 90:10:0.1. B=ACN/H₂O/TFA90:10:0.1

Unless otherwise stated, analysis of final products was carried out byreverse phase analytical HPLC.

Method A: Waters SunFire column (3.5 μm C18, 3.0×150 mm). Gradientelution (0.5 mL/min) from 10-100% Solvent B for 12 min and then 100%Solvent B for 3 min was used. Solvent A is (95% water, 5% acetonitrile,0.05% TFA) and Solvent B is (5% water, 95% acetonitrile, 0.05% TFA, UV254 nm).

Method B: Waters Acquity UPLC BEH C18, 2.1×50 mm, 1.7-μm particles;Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate;Mobile Phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate;Temperature: 50° C.; Gradient: 0-100% B over 3 minutes, then a0.75-minute hold at 100% B; Flow: 1.11 mL/min.

Method C: Waters Acquity UPLC BEH C18, 2.1×50 mm, 1.7-μm particles;Mobile Phase A: 5:95 acetonitrile:water with 0.1% TFA; Mobile Phase B:95:5 acetonitrile:water with 0.1% TFA; Temperature: 50° C.; Gradient:0-100% B over 3 minutes, then a 0.75-minute hold at 100% B; Flow: 1.11mL/min

Method X: ZORBAX® SB C₁₈ column (4.6×75 mm). Gradient elution (2.5mL/min) from 0-100% Solvent B for 8 min and then 100% Solvent B for 2min was used. Solvent A is (90% water, 10% MeOH, 0.02% H₃PO₄) andSolvent B is (10% water, 90% MeOH, 0.02% H₃PO₄, UV 220 nm).

Intermediate 1 Preparation ofN-(4-chloro-2-(6-hydroxypyrimidin-4-yl)phenyl)-2,2,2-trifluoroacetamide

1A. Preparation ofN-(4-chloro-2-(6-methoxypyrimidin-4-yl)phenyl)-2,2,2-trifluoroacetamide

Et₃N (2.1 mL, 15.3 mmol) was added to a solution of4-chloro-2-(6-methoxypyrimidin-4-yl)aniline (3 g, 12.7 mmol) and TFAA(2.2 mL, 15.3 mmol) in DCM (100 mL). The solution was stirred for 1 h atrt. The solution was then concentrated to about 15 mL volume andpurified by normal phase silica gel chromatography (hexanes-EtOAcgradient) to yieldN-(4-chloro-2-(6-methoxypyrimidin-4-yl)phenyl)-2,2,2-trifluoroacetamide(4 g, 12.06 mmol, 95% yield) as a white powder.

1B. Preparation ofN-(4-chloro-2-(6-hydroxypyrimidin-4-yl)phenyl)-2,2,2-trifluoroacetamide

A clear, orange solution ofN-(4-chloro-2-(6-methoxypyrimidin-4-yl)phenyl)-2,2,2-trifluoroacetamide(3.2 g, 9.65 mmol) in HOAc (20 ml) and 48% aq HBr (5.5 ml, 48.2 mmol)was warmed to 60° C. for 1.5 h. The reaction was cooled to rt and thesolvents were removed in vacuo. EtOAc (100 mL) and sat aq NaHCO₃ wereadded to the residue. The aqueous layer was then extracted twice withEtOAc (50 mL). The combined organic layers were dried with MgSO₄ andconcentrated. The residue was triturated with Et₂O and filtered to yieldN-(4-chloro-2-(6-hydroxypyrimidin-4-yl)phenyl)-2,2,2-trifluoroacetamide(1.2 g, 3.78 mmol, 39.2% yield) as a white powder.

Intermediate 2 Preparation of (R)-2-methylbut-3-enoic acid

2A. Preparation of(R)-4-benzyl-3-((R)-2-methylbut-3-enoyl)oxazolidin-2-one

To the solution of 2-methylbut-3-enoic acid (5.59 g, 55.9 mmol) and NMM(6.14 mL, 55.9 mmol) in THF (62 mL) at 0° C. was added pivaloyl chloride(6.87 mL, 55.9 mmol) dropwise. The reaction mixture was cooled down to−78° C., and stirred for ˜2 h. In a separate flask: To the solution of(R)-4-benzyloxazolidin-2-one (8.25 g, 46.6 mmol) in THF (126 mL) at −78°C. was added 2.5 M nBuLi in hexane (20.49 mL, 51.2 mmol) dropwise. After35 min, this reaction was transferred via cannula to the first reaction.The reaction mixture was stirred at −78° C. for 2 h, then the cold bathwas removed, and the reaction was quenched with sat NH₄Cl. The reactionwas diluted with water and extracted with EtOAc (3×). The combinedorganic layers were washed with brine, dried over Na₂SO₄, filtered, andconcentrated to give a yellow oil (15 g). Purification by silica gelchromatography afforded(R)-4-benzyl-3-((R)-2-methylbut-3-enoyl)oxazolidin-2-one (6.59 g, 55%)as a colorless oil. MS(ESI) m/z: 282.1 (M+Na)⁺. ¹H NMR (500 MHz, CDCl₃)δ 7.36-7.19 (m, 5H), 6.03-5.93 (m, 1H), 5.23-5.10 (m, 2H), 4.69-4.63 (m,1H), 4.51-4.43 (m, 1H), 4.23-4.15 (m, 2H), 3.29 (dd, J=13.5, 3.3 Hz,1H), 2.79 (dd, J=13.5, 9.6 Hz, 1H), 1.35 (d, J=6.9 Hz, 3H) ppm. Theother diastereomer(R)-4-benzyl-3-((S)-2-methylbut-3-enoyl)oxazolidin-2-one (4.6 g, 38%)was also obtained as a white solid. MS(ESI) m/z: 260.1 (M+H)⁺.

2B. Preparation of (R)-2-methylbut-3-enoic acid

To a clear colorless solution of(R)-4-benzyl-3-((R)-2-methylbut-3-enoyl) oxazolidin-2-one (6.05 g, 23.33mmol) in THF (146 mL) at 0° C. was added dropwise 30% aq H₂O₂ (9.53 mL,93 mmol) followed by 2 N LiOH (23.33 mL, 46.7 mmol). After 30 min, thereaction was quenched with 25 mL of sat Na₂SO₃ and 25 mL of sat NaHCO₃.The reaction was then concentrated to remove the THF. The residue wasdiluted with water and extracted with CHCl₃ (3×). The aqueous layer wasacidified with conc. HCl to pH˜3 and then it was extracted with EtOAc(3×). The EtOAc layers were combined, washed with brine, dried overMgSO₄, filtered and concentrated to afford (R)-2-methylbut-3-enoic acid(2.15 g, 92%) as a colorless oil. ¹H NMR (500 MHz, CDCl₃) δ 10.84 (br.s., 1H), 5.94 (ddd, J=17.4, 10.1, 7.4 Hz, 1H), 5.22-5.13 (m, 2H),3.23-3.15 (m, 1H), 1.31 (d, J=7.2 Hz, 3H) ppm.

Intermediate 3 Preparation of 6-(3-chloro-2-fluorophenyl)pyrimidin-4-ol

A microwave vial containing 6-chloropyrimidin-4-ol (0.100 g, 0.766mmol), (3-chloro-2-fluorophenyl)boronic acid (0.534 g, 3.06 mmol), andPd(PPh₃)₄ (0.089 g, 0.077 mmol) was purged with Ar for several min. Thendegassed toluene (1.53 mL) and EtOH (1.53 mL) were added followed byDIEA (0.54 mL, 3.06 mmol). The vial was capped and the reaction wasmicrowaved at 120° C. for 1 h. The resulting clear, orange solution wasallowed to cool to rt and a precipitate formed. The yellow solid wasremoved by filtration, rinsing with 1:1 toluene/EtOH. A precipitateformed in the filtrate. The solid was collected by filtration, rinsedwith cold 1:1 toluene/EtOH, air-dried, and dried under vacuum to give6-(3-chloro-2-fluorophenyl)pyrimidin-4-ol (0.0357 g, 21% yield) as awhite solid. MS(ESI) m/z: 225.1 (M+H)⁺ and 227.1 (M+2+H)⁺. ¹H NMR (500MHz, DMSO-d₆) δ 12.71 (br. s., 1H), 8.31 (d, J=1.1 Hz, 1H), 7.87 (ddd,J=8.0, 7.2, 1.7 Hz, 1H), 7.74-7.69 (m, 1H), 7.36 (td, J=8.0, 1.1 Hz,1H), 6.72 (br. s, 1H). ¹⁹F NMR (471 MHz, DMSO-d₆) δ −117.48.

Intermediate 4 Preparation of6-(3-chloro-2,6-difluorophenyl)pyrimidin-4-ol, hydrobromide

4A. Preparation of 4-(3-chloro-2,6-difluorophenyl)-6-methoxypyrimidine

A flask containing 4-chloro-6-methoxypyrimidine (1.0 g, 6.92 mmol),(3-chloro-2,6-difluorophenyl)boronic acid (1.996 g, 10.38 mmol), and 2ndgeneration XPhos precatalyst (0.272 g, 0.346 mmol) was purged with Arfor several min, then degassed THF (13.84 mL) and degassed 0.5 M K₃PO₄(27.7 mL, 13.84 mmol) were added. The resulting cloudy, pink reactionmixture was stirred vigorously at rt. After 2 h, the reaction wasdiluted with water and extracted with EtOAc (2×). The organic layerswere combined and washed with brine, dried over Na₂SO₄, filtered andconcentrated to give an orange-brown residue weighing 1.5 g.Purification by normal phase chromatography gave4-(3-chloro-2,6-difluorophenyl)-6-methoxypyrimidine (0.242 g, 13.6%yield) as an off-white solid. MS(ESI) m/z: 257.0 (M+H)⁺ and 259.0(M+2+H)⁺. ¹H NMR (500 MHz, CD₃OD) δ 8.86 (d, J=1.1 Hz, 1H), 7.68-7.63(m, 1H), 7.17 (td, J=9.0, 1.8 Hz, 1H), 7.10-7.08 (m, 1H), 4.07 (s, 3H).¹⁹F NMR (471 MHz, CD₃OD) δ −115.84 (d, J=4.3 Hz), −116.49 (d, J=5.7 Hz).

4B. Preparation of 6-(3-chloro-2,6-difluorophenyl)pyrimidin-4-ol

A clear, yellow solution of4-(3-chloro-2,6-difluorophenyl)-6-methoxypyrimidine (0.240 g, 0.935mmol) in AcOH (9.35 mL) and 48% aq HBr (5.29 mL, 46.8 mmol) was warmedto 85° C. After 1 h, the reaction was cooled to rt and then it wasconcentrated to give a yellow solid. Et₂O (10 mL) was added resulting ina suspension. The solid was collected by filtration, rinsed with Et₂O,air-dried, and then dried under vacuum to give6-(3-chloro-2,6-difluorophenyl)pyrimidin-4-ol (0.258 g, 85% yield) as anoff-white solid. MS(ESI) m/z: 243.0 (M+H)⁺ and 245.0 (M+2+H)⁺. ¹H NMR(500 MHz, DMSO-d₆) δ 8.33 (d, J=1.1 Hz, 1H), 7.77 (td, J=8.7, 5.6 Hz,1H), 7.32 (td, J=9.1, 1.7 Hz, 1H), 6.63 (d, J=0.6 Hz, 1H). ¹⁹F NMR (471MHz, DMSO-d₆) δ −113.79 (d, J=4.3 Hz), −113.88 (d, J=5.7 Hz).

Intermediate 5 Preparation of 6-(5-chloro-2-fluorophenyl)pyrimidin-4-ol

5A. Preparation of 4-(5-chloro-2-fluorophenyl)-6-methoxypyrimidine

A microwave vial containing 4-chloro-6-methoxypyrimidine (0.290 g, 2.007mmol), (5-chloro-2-fluorophenyl)boronic acid (0.35 g, 2.007 mmol) andNa₂CO₃ (0.213 g, 2.007 mmol) in DME (10 mL), EtOH (1.250 mL) and water(1.250 mL) was purged with N₂ for several min. Then PdCl₂(dppf)-CH₂Cl₂adduct (0.082 g, 0.100 mmol) was added and the vial was capped. Thereaction was heated in a microwave at 100° C. for 1 h. The reactionmixture was then diluted with water and extracted with EtOAc. Theorganic layer was washed with brine and then concentrated to give anorange-brown residue. Purification by normal phase chromatography gave4-(5-chloro-2-fluorophenyl)-6-methoxypyrimidine (400 mg, 84% yield) aswhite crystals. MS(ESI) m/z: 239.3 (M+H)⁺. ¹H NMR (400 MHz, CDCl₃) δ8.86 (s, 1H), 8.16 (dd, J=6.7, 2.8 Hz, 1H), 7.39 (ddd, J=8.8, 4.2, 2.9Hz, 1H), 7.28-7.23 (m, 1H), 7.12 (dd, J=10.8, 8.8 Hz, 1H), 4.04 (s, 3H).

5B. Preparation of 6-(5-chloro-2-fluorophenyl)pyrimidin-4-ol

A clear, yellow solution of4-(5-chloro-2-fluorophenyl)-6-methoxypyrimidine (300 mg, 1.257 mmol) inAcOH (12.57 mL) and 48% aq HBr (7 mL, 61.9 mmol) was warmed to 85° C.After 0.5 h, the reaction was cooled to rt and concentrated under highvacuum to dryness. To the residue was added sat NaHCO₃ carefully to givea suspension. The solid was collected by filtration, rinsed with water,a small amount of acetone and air dried to give6-(5-chloro-2-fluorophenyl)pyrimidin-4-ol (140 mg, 36.5% yield) as awhite solid. MS(ESI) m/z: 225.2 (M+H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ12.73 (br. s., 1H), 8.33 (d, J=0.9 Hz, 1H), 7.99 (dd, J=6.6, 2.9 Hz,1H), 7.61 (ddd, J=6.6, 4.3, 2.1 Hz, 1H), 7.43 (dd, J=11.1, 8.9 Hz, 1H),6.76 (s, 1H).

Intermediate 6 Preparation of(S)-(2-(1-((tert-butoxycarbonyl)amino)but-3-en-1-yl)pyridin-4-yl)boronic acid

6A. Preparation of4-chloro-2-[(E)-2-[(S)-2-methylpropane-2-sulfinyl]ethenyl]pyridine

To a solution of S-(−)-t-butyl-sulfinamide (0.856 g, 7.06 mmol) in DCM(14.1 mL) was added sequentially CuSO₄ (2.481 g, 15.54 mmol) and4-chloropicolinaldehyde (1.0 g, 7.06 mmol). The resulting whitesuspension was stirred at rt. After 3 h, the brown suspension wasfiltered through CELITE®, eluting with DCM, to give a clear brownfiltrate. Concentration of the filtrate gave a brown oil weighing 1.85g. Purification by normal phase chromatography gave 1.31 g of4-chloro-2-[(E)-2-[(S)-2-methylpropane-2-sulfinyl]ethenyl]pyridine as aclear, yellow oil. MS(ESI) m/z: 245.0 (M+H)⁺.

6B. Preparation of(S)—N—((S)-1-(4-chloropyridin-2-yl)but-3-enyl)-2-methylpropane-2-sulfinamide

To a cooled (0-5° C.) mixture of InCl₃ (13.56 g, 61.3 mmol) in THF (170mL) was added dropwise over 30 min 1 M allylmagnesium bromide in Et₂O(62 mL, 61.3 mmol). The reaction was allowed to warm to rt. After 1 h atrt, a solution ofchloro-2-[(E)-2-[(S)-2-methylpropane-2-sulfinyl]ethenyl]pyridine (10 g,40.9 mmol) in EtOH (170 mL) was added. After 3 h, the reaction wasconcentrated under vacuum at 50-55° C. The crude material waspartitioned between EtOAc (200 mL) and water (50 mL) and the layers wereseparated. The aqueous layer was extracted with EtOAc (2×50 mL). Theorganic layers were combined and washed with brine (100 mL), dried overNa₂SO₄, filtered and concentrated to give(S)—N—((S)-1-(4-chloropyridin-2-yl)but-3-enyl)-2-methylpropane-2-sulfinamide(13.5 g, 106%) as a yellow oil. MS(ESI) m/z: 287.2 (M+H)⁺.

6C. Preparation of (S)-tert-butyl1-(4-chloropyridin-2-yl)but-3-enylcarbamate

(S)—N—((S)-1-(4-Chloropyridin-2-yl)but-3-enyl)-2-methylpropane-2-sulfinamide(75 g, 261 mmol) was dissolved in MeOH (1500 mL). 6 N aq HCl (750 mL,4.5 mol) was added. The reaction was stirred at rt for 3 h and then wasconcentrated. The residue was diluted with water (2 L), washed withEtOAc (500 mL). The aqueous layer was basified with sat Na₂CO₃ solutionand then extracted with EtOAc (3×1 L). The combined organic layers werewashed with water (1 L) and brine (1 L), dried over Na₂SO₄, filtered andconcentrated under vacuum at 50-55° C. to give crude product (43 g,90%). MS(ESI) m/z: 183.2 (M+H)⁺. The crude product (42 g, 230 mmol) wasdissolved in DCM (420 mL) and Et₃N (32.1 mL, 230 mmol) was addedfollowed by dropwise addition of Boc₂O (53.4 mL, 230 mmol). The reactionwas stirred at rt for 3 h. The reaction was diluted with DCM (1 L),washed with water (500 mL) and brine (500 mL). The organic layer wasdried over Na₂SO₄, filtered, and concentrated. The crude product wasthen purified using silica gel chromatography to give (S)-tert-butyl1-(4-chloropyridin-2-yl)but-3-enylcarbamate (61 g, 86%) as a pale yellowsolid. MS(ESI) m/z: 283.2 (M+H)⁺.

6D. Preparation of(S)-(2-(1-((tert-butoxycarbonyl)amino)but-3-en-1-yl)pyridin-4-yl)boronicacid trifluoroacetate

To a solution of 5,5,5′,5′-tetramethyl-2,2′-bi(1,3,2-dioxaborinane)(1.198 g, 5.30 mmol) and (S)-tert-butyl1-(4-chloropyridin-2-yl)but-3-enylcarbamate (1.0 g, 3.54 mmol), preparedas described in Intermediate 23, in DMSO (10 mL) was added KOAc (1.041g, 10.61 mmol) and PdCl₂(dppf)-CH₂Cl₂ adduct (0.289 g, 0.354 mmol). Thereaction was purged with Ar for 10 min. The reaction mixture was thensealed and stirred for 12 h at 85° C. The reaction mixture was cooled tort and then it was diluted with EtOAc and washed with water. The aqueouslayer was extracted with EtOAc. The organic layers were combined and waswashed with brine, dried over Na₂SO₄, filtered, and concentrated.Purification by reverse phase chromatography afforded the(S)-(2-(1-((tert-butoxycarbonyl)amino)but-3-en-1-yl)pyridin-4-yl)boronicacid trifluoroacetate (1.1 g, 77%) as a white solid. MS(ESI) m/z: 293.2(M+H)⁺. ¹H NMR (500 MHz, CD₃OD) δ 8.54 (d, J=5.8 Hz, 1H), 8.11 (s, 1H),8.02 (dd, J=5.8, 0.6 Hz, 1H), 5.79 (ddt, J=17.1, 10.2, 7.1 Hz, 1H),5.11-5.03 (m, 2H), 4.86 (t, J=7.0 Hz, 1H), 2.69-2.55 (m, 2H), 1.40 (br.s., 9H) ppm.

Intermediate 7 Preparation of6-(3-chloro-2-fluoro-6-(1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol

7A. Preparation of N-(4-chloro-3-fluorophenyl)-2,2,2-trifluoroacetamide

To a cooled (−10° C.) suspension of 4-chloro-3-fluoroaniline (10.67 g,73.3 mmol) and Na₂CO₃ (13.21 g, 125 mmol) in Et₂O (300 mL) was addeddropwise TFAA (12.23 mL, 88 mmol). The mixture was allowed to warm to rtovernight. The mixture was diluted with hexane (300 mL) and filtered.The filtrate was washed with ice water, 10% aq NaHCO₃, and brine, driedover Na₂SO₄, filtered, and concentrated to giveN-(4-chloro-3-fluorophenyl)-2,2,2-trifluoroacetamide (17 g, 96% yield),as a pale, yellow solid. MS(ESI) m/z: 242.1 (M+H)⁺.

7B. Preparation of(3-chloro-2-fluoro-6-(2,2,2-trifluoroacetamido)phenyl)boronic acid

To a cooled (−78° C.) clear, colorless solution ofN-(4-chloro-3-fluorophenyl)-2,2,2-trifluoroacetamide (0.500 g, 2.070mmol) in THF (8.28 mL) was added dropwise 2.5 M nBuLi in hexane (1.74mL, 4.35 mmol) over 15 min keeping the internal temperature below −65°C. The resulting clear, yellow solution was stirred at −78° C. for 10min. The reaction was allowed to warm to −50° C. over 1 h. The reactionwas then cooled to −78° C. and B(O-i-Pr)₃ (1.051 mL, 4.55 mmol) wasadded dropwise. The reaction was stirred at −78° C. for 30 min and thenthe ice bath was removed and the reaction was allowed to warm to rt andstirred at rt for 1 h. After this time, the reaction was cooled to −5°C. and then quenched with the dropwise addition of 1.0 M HCl (5 mL)followed by the addition of water (5 mL). The resulting cloudy yellowreaction mixture was stirred at rt for 45 min. The reaction was dilutedwith EtOAc and the layers were separated. The organic layer was washedwith brine, dried over Na₂SO₄, filtered and concentrated to give a pale,orange solid. The solid was partitioned between THF (10 mL) and 0.5 MHCl (20 mL) and stirred vigorously for 4 h. The layers were thenseparated and the clear, colorless aqueous layer was concentrated togive (3-chloro-2-fluoro-6-(2,2,2-trifluoroacetamido)phenyl)boronic acid(0.1599 g, 34.2% yield) as a white solid. MS(ESI) m/z: 189.9 [M+H]⁺.

7C. Preparation of 4-chloro-3-fluoro-2-(6-methoxypyrimidin-4-yl)aniline

4-Chloro-3-fluoro-2-(6-methoxypyrimidin-4-yl)aniline was preparedaccording to the procedures described in Intermediate 3 using(3-chloro-2-fluoro-6-(2,2,2-trifluoroacetamido)phenyl)boronic acid.MS(ESI) m/z: 253.9 (M+H)⁺. ¹H NMR (500 MHz, CD₃OD) δ 8.82 (d, J=1.1 Hz,1H), 7.18 (dd, J=8.8, 8.3 Hz, 1H), 7.01 (dd, J=3.0, 1.1 Hz, 1H), 6.61(dd, J=8.9, 1.5 Hz, 1H), 4.04 (s, 3H). ¹⁹F NMR (471 MHz, CD₃OD) δ−119.92 (s, 1F).

7D. Preparation of4-(3-chloro-2-fluoro-6-(1H-1,2,3-triazol-1-yl)phenyl)-6-methoxypyrimidinetrifluoroacetate

In a microwave vial,4-chloro-3-fluoro-2-(6-methoxypyrimidin-4-yl)aniline (0.045 g, 0.177mmol) in CH₃CN (1.8 mL), cooled to 0° C., was added isoamylnitrite(0.036 mL, 0.266 mmol), followed by the dropwise addition of TMSN₃(0.035 mL, 0.266 mmol). Gas evolution was observed. After 5 min, thecold bath was removed, and the reaction was allowed to warm to rt. After1 h, trimethylsilylacetylene (0.076 mL, 0.532 mmol) was added. Theseptum was replaced with a microwave cap and sealed. The reaction washeated in a microwave at 120° C. for a total of 4 h. The reaction wasconcentrated almost to dryness and then purified by reverse phasechromatography to give4-(3-chloro-2-fluoro-6-(1H-1,2,3-triazol-1-yl)phenyl)-6-methoxypyrimidine(27 mg, 0.088 mmol) as a clear glass. MS(ESI) m/z: 306.3 (M+H)⁺. ¹H NMR(400 MHz, CDCl₃) δ 8.74 (d, J=0.4 Hz, 1H), 7.80 (d, J=0.9 Hz, 1H),7.77-7.69 (m, 2H), 7.38 (dd, J=8.6, 1.5 Hz, 1H), 6.88 (s, 1H), 4.06 (s,3H). ¹⁹F NMR (376 MHz, CDCl₃) δ −76.02 (s), −112.27 (s).

7E. Preparation of6-(3-chloro-2-fluoro-6-(1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol

6-(3-Chloro-2-fluoro-6-(1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol wasprepared according to the procedures in described in Intermediate 5 forthe synthesis of 6-(5-chloro-2-fluorophenyl)pyrimidin-4-ol, by replacing4-(5-chloro-2-fluorophenyl)-6-methoxypyrimidine with4-(3-chloro-2-fluoro-6-(1H-1,2,3-triazol-1-yl)phenyl)-6-methoxypyrimidine.MS(ESI) m/z: 292.3 (M+H)⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.20 (d, J=1.1 Hz,1H), 8.06 (d, J=0.7 Hz, 1H), 7.89-7.81 (m, 1H), 7.80 (d, J=0.9 Hz, 1H),7.54 (dd, J=8.6, 1.5 Hz, 1H), 6.52 (s, 1H).

Intermediate 8 Preparation of6-(5-chloro-2-(1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol

8A. Preparation of 4-chloro-2-(6-methoxypyrimidin-4-yl)aniline

4-Chloro-2-(6-methoxypyrimidin-4-yl)aniline was synthesized according tothe procedure described in Intermediate 5, by replacing(5-chloro-2-fluorophenyl)boronic acid with4-chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline. MS(ESI)m/z: 236.3 (M+H)⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.78 (s, 1H), 7.49 (d,J=2.4 Hz, 1H), 7.15 (dd, J=8.6, 2.4 Hz, 1H), 6.99 (d, J=0.9 Hz, 1H),6.66 (d, J=8.6 Hz, 1H), 4.02 (s, 3H).

8B. Preparation of6-(5-chloro-2-(1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol

6-(5-Chloro-2-(1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol wassynthesized according to the procedures described for the synthesis of6-(3-chloro-2-fluoro-6-(1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol, byreplacing 4-chloro-3-fluoro-2-(6-methoxypyrimidin-4-yl)aniline with4-chloro-2-(6-methoxypyrimidin-4-yl)aniline. MS(ESI) m/z: 274.3 (M+H)⁺.¹H NMR (400 MHz, CD₃OD) δ 8.51 (d, J=0.9 Hz, 1H), 8.35 (d, J=1.1 Hz,1H), 7.92 (d, J=1.1 Hz, 1H), 7.88 (d, J=2.4 Hz, 1H), 7.83-7.78 (m, 1H),7.74-7.69 (m, 1H), 6.39 (d, J=0.9 Hz, 1H).

Intermediate 9 Preparation of6-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]pyrimidin-4-ol

9A. Preparation of4-chloro-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)aniline

In a 20 mL microwave vial was added 2-bromo-4-chloroaniline (3 g, 14.53mmol),4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane(5.53 g, 21.80 mmol), KOAc (3.66 g, 37.3 mmol), Pd(dppf)Cl₂—CH₂Cl₂adduct (0.32 g, 0.44 mmol) and DMSO (9 mL). The resulting suspension waspurged with N₂, capped and heated at 80° C. for 22 h. The reaction wascooled to rt. Water was added to dissolve the salts, then the reactionwas filtered. The remaining solid was suspended in DCM and the insolublesolid was filtered. The filtrate was concentrated and then purified bynormal phase chromatography to give4-chloro-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (3.15 g, 86%yield) as a white solid. MS(ESI) m/z: 172.3 (M-C₆H₁₀+H)⁺. ¹H NMR (400MHz, CDCl₃) δ 7.54 (d, J=2.6 Hz, 1H), 7.13 (dd, J=8.8, 2.6 Hz, 1H), 6.52(d, J=8.6 Hz, 1H), 4.72 (br. s., 2H), 1.34 (s, 12H).

9B. Preparation of 4-chloro-2-(6-methoxypyrimidin-4-yl)aniline

A RBF containing 4-chloro-6-methoxypyrimidine (3.13 g, 21.62 mmol),4-chloro-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (7.31 g, 21.62mmol), Na₂C₀₃ (2.29 g, 21.62 mmol), DME (86 ml), EtOH (10.81 ml) andwater (10.81 ml) was equipped with a condenser. The mixture was purgedwith Ar for several min then Pd(dppf)Cl₂—CH₂Cl₂ adduct (1.77 g, 2.16mmol) was added. The reaction was heated at 90° C. for 5 h. The reactionwas cooled to rt, diluted with water and extracted with EtOAc. Theorganic layer was washed with brine, concentrated and purified by normalphase chromatography to give 4-chloro-2-(6-methoxypyrimidin-4-yl)aniline(2.86 g, 56.1% yield) as yellow solid. MS(ESI) m/z: 236.0 (M+H)⁺. ¹H NMR(500 MHz, CDCl₃) δ 8.78 (d, J=1.1 Hz, 1H), 7.49 (d, J=2.5 Hz, 1H), 7.15(dd, J=8.8, 2.5 Hz, 1H), 6.99 (d, J=1.1 Hz, 1H), 6.67 (d, J=8.8 Hz, 1H),5.89 (br. s., 2H), 4.03 (s, 3H).

9C. Preparation of4-{5-chloro-2-[4-(trimethylsilyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-methoxypyrimidine

To a solution of 4-chloro-2-(6-methoxypyrimidin-4-yl)aniline (1.5 g,6.36 mmol) in ACN (90 ml) at 0° C. was added 3-methylbutyl nitrite (1.28ml, 9.55 mmol), followed by the dropwise addition of TMSN₃ (1.26 ml,9.55 mmol). Gas evolution was observed. After 10 min, the ice bath wasremoved, and the reaction was allowed to warm to rt. After 1 h,ethynyltrimethylsilane (2.72 ml, 19.09 mmol) and Cu₂O (0.09 g, 0.64mmol) were added and the reaction was stirred for an additional 1 h. Thereaction was partitioned in EtOAc and sat NH₄Cl, and the layers wereseparated. The organic layer was washed with brine, dried over MgSO₄,filtered and concentrated. Purification by normal phase chromatographygave4-{5-chloro-2-[4-(trimethylsilyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-methoxypyrimidine(2.13 g, 5.92 mmol, 93% yield) as a yellow solid. MS(ESI) m/z: 360.3(M+H)⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.71 (d, J=1.1 Hz, 1H), 7.82 (d, J=2.2Hz, 1H), 7.61-7.56 (m, 1H), 7.54-7.48 (m, 2H), 6.20 (d, J=1.1 Hz, 1H),3.92 (s, 3H), 0.32-0.28 (m, 9H).

9D. Preparation of4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-methoxypyrimidine

To a solution of4-{5-chloro-2-[4-(trimethylsilyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-methoxypyrimidine(1.56 g, 4.33 mmol) in ACN (28.9 ml) was added NCS (2.03 g, 15.17 mmol)and silica gel (6.51 g, 108 mmol). The reaction was stirred at 80° C.for 1 h. Then, the reaction was filtered to remove the silica gel andthe collected silica gel was washed with EtOAc. The filtrate was washedwith water (2×), brine and concentrated. Purification by normal phasechromatography gave4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-methoxypyrimidine(0.90 g, 64.5% yield) as a yellow foam. MS(ESI) m/z: 322.3 (M+H)⁺. ¹HNMR (400 MHz, CDCl₃) δ 8.70 (d, J=1.1 Hz, 1H), 7.75 (d, J=2.4 Hz, 1H),7.66-7.55 (m, 2H), 7.50 (d, J=8.6 Hz, 1H), 6.52 (d, J=0.9 Hz, 1H), 3.98(s, 3H).

9E. Preparation of6-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]pyrimidin-4-ol

To a solution of4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-methoxypyrimidine(900 mg, 2.79 mmol) in AcOH (6 ml) was added 48% aq HBr (3 ml, 26.5mmol). The mixture was stirred at 85° C. for 1 h. The reaction wasconcentrated to dryness and then partitioned between EtOAc and satNaHCO₃. The mixture was separated and the aqueous layer was extractedwith EtOAc (2×). The organic layers were combined, concentrated, andthen the residue was purified by normal phase chromatography to give awhite solid. The solid was suspended in Et₂O, filtered and washed withEt₂O to give6-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]pyrimidin-4-ol (610mg, 70.9% yield) as a white solid. MS(ESI) m/z: 308.3 (M+H)⁺. ¹H NMR(400 MHz, CDCl₃) δ 7.96 (s, 1H), 7.74-7.67 (m, 2H), 7.62 (dd, J=8.5, 2.3Hz, 1H), 7.47 (d, J=8.4 Hz, 1H), 6.44 (d, J=0.9 Hz, 1H).

Intermediate 10 Preparation of6-(3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl)pyrimidin-4-ol

10A. Preparation of N-(4-chloro-3-fluorophenyl)-2,2,2-trifluoroacetamide

To a suspension of 4-chloro-3-fluoroaniline (10.67 g, 73.3 mmol) andNa₂CO₃ (24.5 g, 125 mmol) in Et₂O (300 mL) at −10° C. under N₂ was addedTFAA (12.23 mL, 88 mmol) dropwise. The mixture was allowed to warm to rtand then stirred for 18 h. The reaction mixture was diluted with hexane(300 mL) and filtered. The filtrate was washed with ice water, 10% aqNaHCO₃, and brine, dried over Na₂SO₄, and concentrated. A pale yellowsolid obtained as N-(4-chloro-3-fluorophenyl)-2,2,2-trifluoroacetamide(17 g, 96% yield). MS(ESI) m/z: 242.1 (M+H)⁺.

10B. Preparation of (6-amino-3-chloro-2-fluorophenyl)boronic acid

To a cooled (−78° C.) clear, colorless solution ofN-(4-chloro-3-fluorophenyl)-2,2,2-trifluoroacetamide (5 g, 20.70 mmol)in THF (69.0 ml) was added dropwise 2.5 M BuLi in hexane (16.56 ml, 41.4mmol) over 15 min, keeping the internal temperature below −60° C. Theresulting clear, yellow solution was stirred at −78° C. for 10 min, thenthe reaction was allowed to warm to −50° C. over 1 h. The resultingclear brown solution was cooled to −78° C. and then B(O-iPr)₃ (10.51 ml,45.5 mmol) was added dropwise. The reaction was stirred at −78° C. for10 min, and then the ice bath was removed and the reaction was allowedto warm to rt. The resulting orange suspension was stirred at rt for 2h, then cooled in ice bath and quenched with 1 N HCl (40 ml). Thereaction mixture was warmed to 40° C. for 1 h and then cooled to rt. Thereaction was diluted with EtOAc and the layers were separated. Theorganic layer was washed with brine and concentrated. Purification bynormal phase chromatography afforded(6-amino-3-chloro-2-fluorophenyl)boronic acid (3 g, 76.6% yield).MS(ESI) m/z: 190.1 (M+H)⁺.

10C. Preparation of 4-chloro-3-fluoro-2-(6-methoxypyrimidin-4-yl)aniline

Reaction was done in a 350 ml pressure bottle. A solution of4-chloro-6-methoxypyrimidine (1.784 g, 12.34 mmol),(6-amino-3-chloro-2-fluorophenyl)boronic acid (3.3 g, 12.34 mmol) intoluene (25 ml) and EtOH (25 ml) was purged with N₂ for several min.DIEA (4.31 ml, 24.68 mmol) followed by Pd(Ph₃P)₄ (1.426 g, 1.234 mmol)were added. The flask was capped and the reaction was heated at 120° C.for 2 h, then cooled to rt, and concentrated. Purification by normalphase chromatography afforded4-chloro-3-fluoro-2-(6-methoxypyrimidin-4-yl)aniline (2 g, 45.2% yield)as a yellow solid. MS(ESI) m/z: 254.0 (M+H)⁺.

10D. Preparation of4-(3-chloro-2-fluoro-6-(4-(trimethylsilyl)-1H-1,2,3-triazol-1-yl)phenyl)-6-methoxypyrimidine

To a cooled (0° C.), clear, yellow solution of4-chloro-3-fluoro-2-(6-methoxypyrimidin-4-yl)aniline (2.1 g, 8.28 mmol)in ACN (118 ml) was added isoamylnitrite (1.67 ml, 12.42 mmol), followedby the dropwise addition of TMSN₃ (1.63 ml, 12.42 mmol). After 10 min,the cold bath was removed, and the reaction was allowed to warm to rt.After 2 h, ethynyltrimethylsilane (3.54 ml, 24.84 mmol) and Cu₂O (0.118g, 0.83 mmol) were added, and the reaction was stirred at rt for 1.5 h.The reaction was then diluted with EtOAc and washed with sat NH₄Cl,brine, dried over MgSO₄, filtered and concentrated to give a brown oil.Purification by normal phase chromatography afforded4-(3-chloro-2-fluoro-6-(4-(trimethylsilyl)-1H-1,2,3-triazol-1-yl)phenyl)-6-methoxypyrimidine(2.71 g, 87% yield) as a brown solid. MS(ESI) m/z: 378.1 (M+H)⁺.

10E. Preparation of4-(3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl)-6-methoxypyrimidine

In a RBF equipped with stirring bar and condenser was added4-(3-chloro-2-fluoro-6-(4-(trimethylsilyl)-1H-1,2,3-triazol-1-yl)phenyl)-6-methoxypyrimidine(2.71 g, 7.17 mmol), NCS (3.35 g, 25.1 mmol), and silica gel (10.77 g,179 mmol), followed by ACN (47.8 ml). The reaction was heated at 80° C.for 1 h, and then cooled to rt. The reaction was filtered, and thefiltrate was concentrated. The residue was redissolved in EtOAc andwashed with sat NaHCO₃, water, brine, and concentrated. Purification bynormal phase chromatography afforded4-(3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl)-6-methoxypyrimidine(1.05 g, 43.0% yield) as a yellow solid. MS(ESI) m/z: 340.0 (M+H)⁺. ¹HNMR (400 MHz, CDCl₃) δ 8.68 (d, J=0.7 Hz, 1H), 7.71-7.62 (m, 2H), 7.37(dd, J=8.6, 1.8 Hz, 1H), 6.84 (s, 1H), 4.02 (s, 3H).

10F. Preparation of6-(3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl)pyrimidin-4-ol

A clear, yellow solution of4-(3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl)-6-methoxypyrimidine(1.05 g, 3.09 mmol) in HOAc (15.43 ml) and 48% aq HBr (17.46 ml, 154mmol) was warmed to 65° C. for 3 h, and then cooled to rt andconcentrated. The yellow gum was suspended in EtOAc and washed with satNaHCO₃ (2×), brine, dried over Na₂SO₄, filtered, and concentrated. Tothe residue was added Et₂O (10 ml), and the resulting suspension wassonicated then filtered. The solid was rinsed with Et₂O (2 ml),air-dried with suction to afford6-(3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl)pyrimidin-4-ol(0.79 g, 78% yield) as a white solid. MS(ESI) m/z: 326.3 (M+H)⁺. ¹H NMR(400 MHz, CD₃OD) δ 8.35 (s, 1H), 8.08 (d, J=0.7 Hz, 1H), 7.85 (dd,J=8.7, 7.6 Hz, 1H), 7.54 (dd, J=8.6, 1.5 Hz, 1H), 6.57 (s, 1H).

Intermediate 11 Preparation of6-(3-chloro-2-fluoro-6-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol

11A. Preparation of4-(3-chloro-2-fluoro-6-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-6-methoxypyrimidine

To a cooled (0° C.), clear, yellow solution of4-chloro-3-fluoro-2-(6-methoxypyrimidin-4-yl)aniline (0.2 g, 0.79 mmol)in ACN (11.26 ml) was added isoamylnitrite (0.16 mL, 1.18 mmol),followed by the dropwise addition of TMSN₃ (0.16 mL, 1.18 mmol). After10 min, the cold bath was removed, and the reaction was allowed to warmto rt. After 2 h, Cu₂O (0.011 g, 0.079 mmol) was added.3,3,3-Trifluoroprop-1-yne (0.5 mL, 0.79 mmol) gas was bubbled in throughthe reaction for 5 min, then the reaction was capped and stirred at rt.After 1 h, the reaction was diluted with EtOAc and washed with satNH₄Cl, brine, dried over MgSO₄, filtered and concentrated to give abrown oil. Purification by normal phase chromatography afforded4-(3-chloro-2-fluoro-6-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-6-methoxypyrimidine(0.24 g, 81% yield) as a yellow solid. MS(ESI) m/z: 374.3 (M+H)⁺.

11B. Preparation of6-(3-chloro-2-fluoro-6-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol

A clear, yellow solution of4-(3-chloro-2-fluoro-6-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-6-methoxypyrimidine(0.1 g, 0.268 mmol) in HOAc (1.34 ml) and 48% aq HBr (1.51 ml, 13.38mmol) was warmed to 65° C. for 3 h, and then cooled to rt andconcentrated. The yellow gum was suspended with EtOAc, washed with satNaHCO₃ (2×), brine, dried over Na₂SO₄, filtered, and concentrated. Tothe residue was added Et₂O (3 ml) and the resulting suspension wassonicated, then filtered. The solid was rinsed with Et₂O (2 ml),air-dried with suction to afford6-(3-chloro-2-fluoro-6-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol(0.07 g, 72.7% yield) as a white solid. MS(ESI) m/z: 360.0 (M+H)⁺. ¹HNMR (400 MHz, CD₃OD) δ 8.84 (s, 1H), 8.03 (br. s., 1H), 7.91-7.84 (m,1H), 7.58 (dd, J=8.8, 1.5 Hz, 1H), 6.61 (br. s., 1H).

Intermediate 12 Preparation of1-(4-chloro-3-fluoro-2-(6-hydroxypyrimidin-4-yl)phenyl)-1H-1,2,3-triazole-4-carbonitrile

12A. Preparation of1-(4-chloro-3-fluoro-2-(6-methoxypyrimidin-4-yl)phenyl)-1H-1,2,3-triazole-4-carboxamide

To a cooled (0° C.), clear, yellow solution of4-chloro-3-fluoro-2-(6-methoxypyrimidin-4-yl)aniline (1 g, 3.94 mmol) inACN (56.3 ml) was added isoamylnitrite (0.79 ml, 5.91 mmol), followed bythe dropwise addition of TMSN₃ (0.79 ml, 5.91 mmol). After 10 min, thecold bath was removed, and the reaction was allowed to warm to rt andstirred at rt for 1 h. Next, propiolamide (0.817 g, 11.83 mmol) and Cu₂₀(0.056 g, 0.394 mmol) were added. After 1 h, the yellow cloudy reactionwas diluted with EtOAc, and washed with sat NH₄Cl, brine, dried overMgSO₄, filtered and concentrated to give a yellow solid. DCM (10 ml) wasadded and the resulting mixture was sonicated. The suspension wasfiltered and the solid was air-dried. A yellow solid obtained as1-(4-chloro-3-fluoro-2-(6-methoxypyrimidin-4-yl)phenyl)-1H-1,2,3-triazole-4-carboxamide(1.003 g, 73.0% yield). MS(ESI) m/z: 349.0 (M+H)⁺.

12B. Preparation of1-(4-chloro-3-fluoro-2-(6-methoxypyrimidin-4-yl)phenyl)-1H-1,2,3-triazole-4-carbonitrile

To a suspension of1-(4-chloro-3-fluoro-2-(6-methoxypyrimidin-4-yl)phenyl)-1H-1,2,3-triazole-4-carboxamide(1.003 g, 2.88 mmol) in EtOAc (13 ml) was added TEA (1.20 ml, 8.63mmol), followed by the dropwise addition of T3P® (50% in EtOAc) (5.14ml, 8.63 mmol). The reaction was microwaved at 120° C. for 30 min andthen it was cooled to rt. The reaction was diluted with EtOAc, washedwith sat NaHCO₃, brine, dried over Na₂SO₄, filtered, and concentrated toafford a brown solid. Purification by normal phase chromatographyafforded1-(4-chloro-3-fluoro-2-(6-methoxypyrimidin-4-yl)phenyl)-1H-1,2,3-triazole-4-carbonitrile(0.815 g, 86% yield) as a yellow solid. MS(ESI) m/z: 331.1 (M+H)⁺. ¹HNMR (400 MHz, CDCl₃) δ 8.62 (d, J=1.1 Hz, 1H), 8.21 (s, 1H), 7.72 (dd,J=8.6, 7.5 Hz, 1H), 7.39 (dd, J=8.6, 1.8 Hz, 1H), 6.89 (dd, J=1.9, 1.2Hz, 1H), 4.03 (s, 3H).

12C. Preparation of1-(4-chloro-3-fluoro-2-(6-hydroxypyrimidin-4-yl)phenyl)-1H-1,2,3-triazole-4-carbonitrile

To a suspension of1-(4-chloro-3-fluoro-2-(6-methoxypyrimidin-4-yl)phenyl)-1H-1,2,3-triazole-4-carbonitrile(0.81 g, 2.449 mmol) in ACN (16.33 ml) was added TMSI (2.00 ml, 14.70mmol) at rt then the clear solution was heated to 50° C. After 18 h, thereaction was cooled to rt. The reaction was poured into a 10% Na₂S₂O₃solution and extracted with EtOAc (3×). The combined organic layers werewashed with sat NaHCO₃, brine, dried over Na₂SO₄, filtered, andconcentrated to give a residue. The residue was suspended in DCM (20ml), filtered, and the solid was rinsed with DCM, and air-dried toafford1-(4-chloro-3-fluoro-2-(6-hydroxypyrimidin-4-yl)phenyl)-1H-1,2,3-triazole-4-carbonitrile(0.73 g, 94% yield) as a white solid. MS(ESI) m/z: 317.1 (M+H)⁺. ¹H NMR(400 MHz, CD₃OD) δ 8.97 (s, 1H), 8.04 (s, 1H), 7.91-7.85 (m, 1H), 7.58(dd, J=8.8, 1.5 Hz, 1H), 6.62 (s, 1H). ¹⁹F NMR (376 MHz, CD₃OD) δ−114.93 (s, 1F).

Intermediate 13 Preparation of6-(5-chloro-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-olhydrobromide

13A. Preparation of4-(5-chloro-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)phenyl)-6-methoxypyrimidine

To a cooled (0° C.), clear, yellow solution of4-chloro-2-(6-methoxypyrimidin-4-yl)aniline (0.100 g, 0.42 mmol) in ACN(6.06 ml) was added isoamylnitrite (0.086 ml, 0.64 mmol), followed bythe dropwise addition of TMSN₃ (0.084 ml, 0.64 mmol). After 10 min, thecold bath was removed, and the reaction was allowed to warm to rt andthe reaction was stirred at rt for 1 h. Next, ethynylcyclopropane (0.120g, 1.27 mmol) and Cu₂O (6.07 mg, 0.042 mmol) were added. The flask wasequipped with a reflux condenser and the reaction was heated to 50° C.for 1 h, then the reaction was cooled to rt. The reaction was dilutedwith DCM and washed with sat NH₄Cl, brine, dried over MgSO₄, filteredand concentrated to give a brown oil. Purification by normal phasechromatography then reverse phase chromatography afforded4-(5-chloro-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)phenyl)-6-methoxypyrimidine(0.024 g, 17.3% yield) as a yellow oil. MS(ESI) m/z: 328.1 (M+H)⁺. ¹HNMR (400 MHz, CDCl₃) δ 8.75 (d, J=0.9 Hz, 1H), 7.79 (d, J=2.2 Hz, 1H),7.61-7.56 (m, 1H), 7.51-7.47 (m, 1H), 7.29 (s, 1H), 6.35 (d, J=0.9 Hz,1H), 3.96 (s, 3H), 1.96 (tt, J=8.4, 5.0 Hz, 1H), 1.02-0.95 (m, 2H),0.88-0.81 (m, 2H).

13B. Preparation of6-(5-chloro-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol hydrobromide

A clear, yellow solution of4-(5-chloro-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)phenyl)-6-methoxypyrimidine(0.024 g, 0.073 mmol) in HOAc (0.73 ml) and 48% aq HBr (0.41 ml, 3.66mmol) was warmed to 65° C. for 3 h, and then cooled to rt andconcentrated. The yellow gum was suspended in EtOAc and washed withbrine, dried over Na₂SO₄, filtered, and concentrated. To the residue wasadded Et₂O (3 ml), sonicated, and filtered. The solid was rinsed withEt₂O (2 ml), air-dried with suction to afford6-(5-chloro-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-olhydrobromide (0.03 g, 100% yield) as a yellow solid. MS(ESI) m/z: 314.0(M+H)⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.67 (d, J=0.7 Hz, 1H), 8.22 (s, 1H),7.89 (d, J=2.4 Hz, 1H), 7.82 (dd, J=8.6, 2.2 Hz, 1H), 7.74 (d, J=8.6 Hz,1H), 6.48 (d, J=0.9 Hz, 1H), 2.11-2.01 (m, 1H), 1.11-1.04 (m, 2H),0.91-0.84 (m, 2H).

Intermediate 14 Preparation of6-(3-chloro-6-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-2-fluorophenyl)pyrimidin-4-ol

14A. Preparation of4-(3-chloro-6-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-2-fluorophenyl)-6-methoxypyrimidine

To a cooled (0° C.), clear, yellow solution of4-chloro-3-fluoro-2-(6-methoxypyrimidin-4-yl)aniline (0.100 g, 0.39mmol) in ACN (5.6 ml) was added isoamylnitrite (0.079 ml, 0.59 mmol),followed by the dropwise addition of TMSN₃ (0.078 ml, 0.59 mmol). After10 min, the cold bath was removed, and the reaction was allowed to warmto rt. After 1 h, ethynylcyclopropane (0.112 g, 1.18 mmol) and Cu₂O(5.64 mg, 0.039 mmol) were added. The flask was equipped with a refluxcondenser and the reaction was heated to 50° C. for 1 h, then thereaction was cooled to rt. The reaction was diluted with DCM and washedwith sat NH₄Cl, brine, dried over MgSO₄, filtered and concentrated togive a brown oil. Purification by normal phase chromatography afforded4-(3-chloro-6-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-2-fluorophenyl)-6-methoxypyrimidine(0.05 g, 36.7% yield) as a yellow oil. MS(ESI) m/z: 346.0 (M+H)⁺. ¹H NMR(400 MHz, CDCl₃) δ 8.69 (d, J=0.9 Hz, 1H), 7.63 (dd, J=8.6, 7.5 Hz, 1H),7.35 (dd, J=8.6, 1.5 Hz, 1H), 7.30 (s, 1H), 6.76 (t, J=1.2 Hz, 1H), 4.00(s, 3H), 1.90 (tt, J=8.4, 5.0 Hz, 1H), 0.98-0.91 (m, 2H), 0.82-0.76 (m,2H).

14B. Preparation of6-(3-chloro-6-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-2-fluorophenyl)pyrimidin-4-ol

A clear, yellow solution of4-(3-chloro-6-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-2-fluorophenyl)-6-methoxypyrimidine(0.05 g, 0.145 mmol) in HOAc (1.45 ml) and 48% aq HBr (0.82 ml, 7.23mmol) was warmed to 65° C. for 3 h, and then the reaction was cooled tort and concentrated. Purification by reverse phase chromatographyafforded6-(3-chloro-6-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-2-fluorophenyl)pyrimidin-4-ol(0.04 g, 83% yield) as a yellow solid. MS(ESI) m/z: 332.0 (M+H)⁺. ¹H NMR(400 MHz, CD₃OD) δ 8.09 (d, J=0.9 Hz, 1H), 7.91 (s, 1H), 7.82 (dd,J=8.6, 7.7 Hz, 1H), 7.49 (dd, J=8.8, 1.5 Hz, 1H), 6.50-6.47 (m, 1H),1.97 (tt, J=8.5, 5.1 Hz, 1H), 1.01-0.95 (m, 2H), 0.81-0.75 (m, 2H). ¹⁹FNMR (376 MHz, CD₃OD) δ −115.39 (s).

Intermediate 15 Preparation of6-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}pyrimidin-4-ol

15A. Preparation of4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-methoxypyrimidine

To a solution of 4-chloro-2-(6-methoxypyrimidin-4-yl)aniline (1.0 g,4.24 mmol), prepared as described in Intermediate 9B, in ACN (60.6 ml)at 0° C. was added 3-methylbutyl nitrite (0.86 ml, 6.36 mmol) followedby the dropwise addition of TMSN₃ (0.84 ml, 6.36 mmol). Gas evolutionwas observed. After 10 min, the ice bath was removed, and the reactionwas allowed to warm to rt. After 2 h, Cu₂O (61 mg, 0.42 mmol) was addedfollowed by a slow bubbling of 3,3,3-trifluoroprop-1-yne gas over aperiod of 5 min. After an additional 10 min, the reaction waspartitioned between DCM and sat NH₄Cl and then the layers wereseparated. The organic layer was washed with brine, dried over MgSO₄,filtered and concentrated. Purification by normal phase chromatographygave4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-methoxypyrimidine(1.46 g, 97% yield) as a yellow solid. MS(ESI) m/z: 356.1 (M+H)⁺. ¹H NMR(400 MHz, CDCl₃) δ 8.62 (d, J=1.1 Hz, 1H), 8.00 (d, J=0.7 Hz, 1H), 7.75(d, J=2.4 Hz, 1H), 7.66-7.60 (m, 1H), 7.52 (d, J=8.6 Hz, 1H), 6.60 (d,J=1.1 Hz, 1H), 3.98 (s, 3H). ¹⁹F NMR (376 MHz, CDCl₃) δ −61.10 (s).

15B. Preparation of6-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}pyrimidin-4-ol

To a solution of4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-methoxypyrimidine(1.46 g, 4.10 mmol) in AcOH (10 ml) was added 48% aq HBr (5 ml, 44.2mmol). The mixture was stirred at 85° C. for 1 h. The reaction wasconcentrated to dryness and then partitioned between EtOAc and satNaHCO₃. The layers were separated and the aqueous layer was extractedwith EtOAc (2×). The organic layers were combined and washed with satNaHCO₃, brine, dried over MgSO₄, filtered and the solvent was reducedunder vacuum until some solid started to form. The resulting suspensionwas triturated with Et₂O. The solid was filtered and washed with Et₂O togive6-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}pyrimidin-4-ol(1 g, 71.3% yield) as a pale yellow solid. MS(ESI) m/z: 342.0 (M+H)⁺. ¹HNMR (400 MHz, CD₃OD) δ 8.83 (d, J=0.7 Hz, 1H), 7.99 (d, J=0.9 Hz, 1H),7.87 (d, J=2.2 Hz, 1H), 7.79-7.72 (m, 1H), 7.70-7.62 (m, 1H), 6.45 (d,J=0.9 Hz, 1H). ¹⁹F NMR (376 MHz, CD₃OD) δ −62.61 (s).

Intermediate 16 Preparation of6-{5-chloro-2-[4-(difluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}pyrimidin-4-ol

16A. Preparation of{1-[4-chloro-2-(6-methoxypyrimidin-4-yl)phenyl]-1H-1,2,3-triazol-4-yl}methanol

{1-[4-Chloro-2-(6-methoxypyrimidin-4-yl)phenyl]-1H-1,2,3-triazol-4-yl}methanol(0.44 g, 52.5% yield) was prepared in a similar manner as the proceduredescribed for the preparation of4-{5-chloro-2-[4-(trimethylsilyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-methoxypyrimidine,as described in Intermediate 9C, by replacing ethynyltrimethylsilanewith propargyl alcohol (0.38 ml, 6.36 mmol). MS(ESI) m/z: 318.3 (M+H)⁺.¹H NMR (400 MHz, CDCl₃) δ 8.66 (d, J=1.1 Hz, 1H), 7.77 (d, J=2.2 Hz,1H), 7.63 (s, 1H), 7.61-7.55 (m, 1H), 7.51-7.46 (m, 1H), 6.42 (d, J=1.1Hz, 1H), 4.77 (d, J=5.9 Hz, 2H), 3.93 (s, 3H).

16B. Preparation of1-[4-chloro-2-(6-methoxypyrimidin-4-yl)phenyl]-1H-1,2,3-triazole-4-carbaldehyde

To a solution of{1-[4-chloro-2-(6-methoxypyrimidin-4-yl)phenyl]-1H-1,2,3-triazol-4-yl}methanol(95 mg, 0.3 mmol) in DMSO (1 mL) was added IBX (92 mg, 0.33 mmol) andthe reaction was stirred at rt for 14 h. Water and sat NaHCO₃ were addedand the mixture was extracted with EtOAc (2×). The organic layers werecombined, concentrated and purified by normal phase chromatography togive 1-[4-chloro-2-(6-methoxypyrimidin-4-yl)phenyl]-1H-1,2,3-triazole-4-carbaldehyde (82 mg, 87%yield) as a white solid. MS(ESI) m/z: 316.3 (M+H)⁺. ¹H NMR (400 MHz,CDCl₃) δ 10.16 (s, 1H), 8.62 (d, J=1.1 Hz, 1H), 8.21 (s, 1H), 7.76 (d,J=2.2 Hz, 1H), 7.64 (dd, J=8.5, 2.3 Hz, 1H), 7.53 (d, J=8.4 Hz, 1H),6.59 (d, J=1.1 Hz, 1H), 3.97 (s, 3H).

16C. Preparation of4-{5-chloro-2-[4-(difluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-methoxypyrimidine

To a solution of1-[4-chloro-2-(6-methoxypyrimidin-4-yl)phenyl]-1H-1,2,3-triazole-4-carbaldehyde(427 mg, 1.35 mmol) in DCM (30 ml) was added DAST (0.54 ml, 4.1 mmol)and the reaction was stirred overnight at rt. The reaction was quenchedwith water and extracted with DCM. The organic layer was concentratedand purified by normal phase chromatography to give4-{5-chloro-2-[4-(difluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-methoxypyrimidine(441 mg, 97% yield) as a yellow solid. MS(ESI) m/z: 338.3 (M+H)⁺. ¹H NMR(400 MHz, CDCl₃) δ 8.65 (d, J=0.9 Hz, 1H), 7.89 (s, 1H), 7.76 (d, J=2.4Hz, 1H), 7.62 (dd, J=8.5, 2.3 Hz, 1H), 7.55-7.47 (m, 1H), 6.89 (t,J=54.6 Hz, 1H), 6.52 (d, J=1.1 Hz, 1H), 4.03-3.87 (m, 3H). ¹⁹F NMR (376MHz, CDCl₃) δ −112.40 (s).

16D. Preparation of6-{5-chloro-2-[4-(difluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}pyrimidin-4-ol

6-{5-Chloro-2-[4-(difluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}pyrimidin-4-ol(370 mg, 88% yield) was prepared in a similar manner as the proceduredescribed for the preparation of6-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]pyrimidin-4-ol, asdescribed in Intermediate 9E, by replacing4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-methoxypyrimidinewith4-{5-chloro-2-[4-(difluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-methoxypyrimidine(441 mg, 1.31 mmol). MS(ESI) m/z: 324.3 (M+H)⁺. ¹H NMR (400 MHz, CDCl₃)δ 8.04 (s, 1H), 7.86 (s, 1H), 7.71 (d, J=2.2 Hz, 1H), 7.67-7.61 (m, 1H),7.51 (d, J=8.6 Hz, 1H), 6.92 (t, J=54.6 Hz, 1H), 6.43 (d, J=0.7 Hz, 1H).¹⁹F NMR (376 MHz, CDCl₃) δ −112.69 (s).

Intermediate 17 Preparation of6-[3-chloro-2-fluoro-6-(1H-1,2,3,4-tetrazol-1-yl)phenyl]pyrimidin-4-ol

17A. Preparation of4-[3-chloro-2-fluoro-6-(1H-1,2,3,4-tetrazol-1-yl)phenyl]-6-methoxypyrimidine

4-Chloro-3-fluoro-2-(6-methoxypyrimidin-4-yl)aniline (300 mg, 1.183mmol) dissolved in AcOH (3 mL) was added trimethoxymethane (377 mg, 3.55mmol), stirred at rt. After 30 min, NaN₃ (231 mg, 3.55 mmol) was addedand stirred at rt for 16 h. To the reaction mixture was added water anda precipitate formed. The mixture was filtered to collect the solidresidue, and filtrate was extracted with EtOAc, and the organic laterwas washed with brine, dried over MgSO₄, filtered and concentrated togive a crude solid, which was then combined with original solid residuecollected. The crude material was purified by normal phasechromatography to afford4-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-6-methoxypyrimidine(367 mg, 100% yield). MS(ESI) m/z: 307.08 (M+H)⁺. ¹H NMR (400 MHz,CDCl₃) δ 8.78 (s, 1H), 8.59 (d, J=1.1 Hz, 1H), 7.71 (dd, J=8.7, 7.4 Hz,1H), 7.38 (dd, J=8.6, 1.8 Hz, 1H), 6.86 (dd, J=1.9, 1.2 Hz, 1H), 3.98(s, 3H).

17B. Preparation of6-[3-chloro-2-fluoro-6-(1H-1,2,3,4-tetrazol-1-yl)phenyl]pyrimidin-4-ol

To a solution of4-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-6-methoxypyrimidine (50mg, 0.163 mmol), NaI (244 mg, 1.630 mmol) dissolved in ACN (1.6 ml) wasadded TMSCl (0.2 ml, 1.630 mmol). The resulting reaction mixture wasstirred at rt for 23 h. To the reaction mixture was added CELITE®, theslurry was filtered and the collected organics were concentrated toyield a crude solid. Purification by normal phase chromatography,followed by trituration with Et₂O, afforded6-[3-chloro-2-fluoro-6-(1H-1,2,3,4-tetrazol-1-yl)phenyl]pyrimidin-4-ol(46 mg, 96% yield) as a white solid. MS(ESI) m/z: 293.08 (M+H)⁺. ¹H NMR(400 MHz, CD₃OD) δ 9.75 (s, 1H), 8.40 (s, 1H), 8.28 (dd, J=8.7, 7.6 Hz,1H), 7.97 (dd, J=8.7, 1.7 Hz, 1H), 7.02 (s, 1H).

Intermediate 18 Preparation of1-[4-chloro-2-(6-hydroxypyrimidin-4-yl)phenyl]-1H-1,2,3-triazole-4-carbonitrile

18A. Preparation of1-[4-chloro-2-(6-methoxypyrimidin-4-yl)phenyl]-1H-1,2,3-triazole-4-carboxamide

1-[4-Chloro-2-(6-methoxypyrimidin-4-yl)phenyl]-1H-1,2,3-triazole-4-carboxamide(300 mg, 80% yield) was prepared in a similar manner as the proceduredescribed for the preparation of4-{5-chloro-2-[4-(trimethylsilyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-methoxypyrimidine,as described in Intermediate 9C, by replacing ethynyltrimethylsilanewith prop-2-ynamide (176 mg, 2.55 mmol). MS(ESI) m/z: 331.4 (M+H)⁺. ¹HNMR (400 MHz, CDCl₃) δ 8.66 (d, J=0.7 Hz, 1H), 8.16 (s, 1H), 7.76 (d,J=2.4 Hz, 1H), 7.62 (dd, J=8.5, 2.3 Hz, 1H), 7.51 (d, J=8.6 Hz, 1H),7.05 (br. s., 1H), 6.53 (d, J=0.9 Hz, 1H), 5.66 (br. s., 1H), 3.97 (s,3H).

18B. Preparation of1-[4-chloro-2-(6-methoxypyrimidin-4-yl)phenyl]-1H-1,2,3-triazole-4-carbonitrile

To a suspension of1-[4-chloro-2-(6-methoxypyrimidin-4-yl)phenyl]-1H-1,2,3-triazole-4-carboxamide(91 mg, 0.28 mmol) and TEA (115 μl, 0.83 mmol) in EtOAc (6.88 ml) wasadded T3P® (50% in EtOAc) (0.49 ml, 0.83 mmol) dropwise. The reactionwas microwaved at 120° C. for 1 h. Additional TEA (115 μl, 0.83 mmol)and T3P® (50% in EtOAc) (0.49 ml, 0.83 mmol) were added and the reactionwas microwaved at 120° C. for an additional 30 min. The reaction wasdiluted with EtOAc and washed with water, sat NaHCO₃, brine, dried overMgSO₄, filtered, and concentrated. Purification by normal phasechromatography gave1-[4-chloro-2-(6-methoxypyrimidin-4-yl)phenyl]-1H-1,2,3-triazole-4-carbonitrile(91 mg, 100% yield) as a white solid. MS(ESI) m/z: 313.3 (M+H)⁺. ¹H NMR(400 MHz, CDCl₃) δ 8.62 (d, J=0.9 Hz, 1H), 8.17 (s, 1H), 7.73 (d, J=2.4Hz, 1H), 7.65 (dd, J=8.5, 2.3 Hz, 1H), 7.51 (d, J=8.6 Hz, 1H), 6.65 (d,J=1.1 Hz, 1H), 4.00 (s, 3H).

18C. Preparation of1-[4-chloro-2-(6-hydroxypyrimidin-4-yl)phenyl]-1H-1,2,3-triazole-4-carbonitrile

To a suspension of1-[4-chloro-2-(6-methoxypyrimidin-4-yl)phenyl]-1H-1,2,3-triazole-4-carbonitrile(91 mg, 0.29 mmol) in ACN (3 mL) was added TMSI (0.2 mL, 1.47 mmol) atrt and the solution was heated at 50° C. for 15 h. The reaction waspoured into 10% Na₂S₂O₃ and sat NaHCO₃ then extracted with EtOAc (3×).The combined organic layers were washed with brine. On standing, a solidprecipitated out from the organic layer. The solid was filtered andrinsed with EtOAc and air-dried to give1-[4-chloro-2-(6-hydroxypyrimidin-4-yl)phenyl]-1H-1,2,3-triazole-4-carbonitrile(60 mg, 69.0% yield) as a white solid. MS(ESI) m/z: 299.3 (M+H)⁺. ¹H NMR(400 MHz, CDCl₃) δ 8.22 (s, 1H), 7.91 (s, 1H), 7.72 (d, J=2.2 Hz, 1H),7.66 (dd, J=8.5, 2.3 Hz, 1H), 7.49 (d, J=8.4 Hz, 1H), 6.55 (s, 1H).

Intermediate 19 Preparation of(9R,13S)-13-amino-9-methyl-3-{[2-(trimethylsilyl)ethoxy]methyl}-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

19A. Preparation of4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole

To a solution of 4-nitro-1H-pyrazole (5.0 g, 44.2 mmol) in THF (100 mL)at 0° C. was added N-cyclohexyl-N-methylcyclohexanamine (0.948 mL, 4.43mmol) followed by dropwise addition of SEM-Cl (12.55 mL, 70.7 mmol). Thereaction mixture was then allowed to gradually warm to rt and stirredovernight. The reaction mixture was concentrated and purified by normalphase chromatography to yield4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole as clear oil(2.4 g, 21% yield). ¹H NMR (500 MHz, CDCl₃) δ 8.31 (s, 1H), 8.10 (s,1H), 5.46 (s, 2H), 3.67-3.55 (m, 2H), 0.99-0.90 (m, 2H), 0.05-0.03 (m,9H).

19B. Preparation of (S)-benzyl(1-(4-(4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate

To a N₂ flushed pressure vial was added (S)-benzyl(1-(4-chloropyridin-2-yl)but-3-en-1-yl)carbamate, prepared as describedin Intermediate 23, (1.9 g, 6.00 mmol),4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole, prepared asdescribed in Intermediate 41A, (1.6 g, 6.60 mmol),di(adamant-1-yl)(butyl)phosphine (0.323 g, 0.90 mmol), PvOH (0.209 mL,1.80 mmol) and K₂CO₃ (2.48 g, 17.9 mmol). To the above mixture was thenadded N,N-dimethylacetamide (45 mL) and the vial was purged with N₂ for5 min. To this mixture was then added Pd(OAc)₂ (0.135 g, 0.600 mmol).The reaction mixture was again purged with N₂. The vial was sealed andheated in microwave at 120° C. for 1 h. The reaction mixture was cooledto rt and partitioned between 10% aqueous LiCl (15 mL) and EtOAc (30mL). The aqueous layer was extracted with EtOAc (2×20 mL) and thecombined organic layers were washed with brine (15 mL) and dried overMgSO₄. The crude product was then purified using normal phasechromatography to yield (S)-benzyl(1-(4-(4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate(1.92 g, 58% yield) as a brown oil. MS(ESI) m/z: 524.2 (M+H)⁺.

19C. Preparation of(S)-benzyl(1-(4-(4-amino-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate

A solution of (S)-benzyl(1-(4-(4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate(1.92 g, 3.68 mmol), prepared as described in Intermediate 41B, in MeOH(20 mL) and AcOH (2 mL) was heated at 40° C. To the above clear solutionwas then slowly added Zn (0.481 g, 7.35 mmol, in 3 portions (50:25:25%))and allowed to stir at the same temperature for 5 min. The reactionmixture was monitored by LCMS and once complete, to the cooled reactionmixture was added 2.0 g of K₂CO₃ (1 g for 1 mL AcOH) and 2 mL water. Thereaction mixture was stirred for 5 min then filtered over a pad ofCELITE® and concentrated to yield the crude product. The crude productwas then partitioned between EtOAc (30 mL) and sat NaHCO₃ (15 mL)solution. The organic layers are separated and dried over MgSO₄,filtered and concentrated. The crude product was then purified usingnormal phase chromatography to yield (S)-benzyl(1-(4-(4-amino-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate(1.15 g, 63% yield) as pale yellow oil. MS(ESI) m/z: 494.4 (M+H)⁺.

19D. Preparation of benzyl((S)-1-(4-(4-((R)-2-methylbut-3-enamido)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate

To a N₂ flushed, 3-necked, 250 mL RBF was added a solution (S)-benzyl(1-(4-(4-amino-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate(1.15 g, 2.33 mmol), prepared as described in Example 41C, and EtOAc (15mL). The solution was cooled to −10° C. and (R)-2-methylbut-3-enoicacid, as prepared in Intermediate 2, (350 mg, 3.49 mmol), pyridine(0.564 mL, 6.99 mmol) and T3P® (2.77 mL, 4.66 mmol) were added. Thecooling bath was removed and the solution was allowed to warm to rt andthen stir over a period of 20 h. Water (20 mL) and EtOAc (20 mL) wereadded and the mixture was stirred for 30 min. The organic phase wasseparated and the aqueous layer was extracted with EtOAc (20 mL). Thecombined organic extracts were washed with brine (15 mL), dried overNa₂SO₄, filtered and concentrated in vacuo. Purification by normal phasechromatography eluting with a gradient of hexanes/EtOAc gave benzyl((S)-1-(4-(4-((R)-2-methylbut-3-enamido)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate (1.12 g,79% yield). MS(ESI) m/z: 576.4 [M+H]⁺.

19E. Preparation of benzylN-[(9R,10E,13S)-9-methyl-8-oxo-3-{[2-(trimethylsilyl)ethoxy]methyl}-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate

To a N₂ flushed, 250 mL, 3-necked, RBF was added a solution of benzyl((S)-1-(4-(4-((R)-2-methylbut-3-enamido)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate(1.12 g, 1.945 mmol), prepared as described in Intermediate 41D, in DCE(18 mL). The solution was sparged with Ar for 15 min. Second GenerationGrubbs Catalyst (662 mg, 0.778 mmol) was added in one portion. Thereaction mixture was heated at 120° C. in microwave for 30 min. Aftercooling to rt, the solvent was removed and the residue was purified bynormal phase chromatography eluting with a gradient of DCM/MeOH to yieldbenzylN-[(9R,10E,13S)-9-methyl-8-oxo-3-{[2-(trimethylsilyl)ethoxy]methyl}-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate(477 mg, 42% yield) as a tan solid. MS(ESI) m/z: 548.3 [M+H]⁺.

19F. Preparation of(9R,13S)-13-amino-9-methyl-3-{[2-(trimethylsilyl)ethoxy]methyl}-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

Pd/C (0.93 g, 0.871 mmol) was added to a 250 mL Parr hydrogenation flaskcontaining a solution of benzylN-[(9R,10E,13S)-9-methyl-8-oxo-3-{[2-(trimethylsilyl)ethoxy]methyl}-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate(477 mg, 0.871 mmol), prepared as described in Intermediate 41E, in EtOH(20 mL). The flask was purged with N₂ and pressurized to 55 psi of H₂and allowed to stir for 4 h. The reaction was filtered through a pad ofCELITE® and concentrated to yield(9R,13S)-13-amino-9-methyl-3-{[2-(trimethylsilyl)ethoxy]methyl}-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(245 mg, 64% yield) as a tan solid. MS(ESI) m/z: 416.4 [M+H]⁺.

Intermediate 20 Preparation of6-[5-chloro-2-(1H-1,2,3,4-tetrazol-1-yl)phenyl]pyrimidin-4-ol

20A. Preparation of4-[5-chloro-2-(1H-1,2,3,4-tetrazol-1-yl)phenyl]-6-methoxypyrimidine

To a solution of 4-chloro-2-(6-methoxypyrimidin-4-yl)aniline (0.507 g,2.151 mmol) dissolved in AcOH (5.4 ml) was added trimethoxymethane(0.685 g, 6.45 mmol) and the resulting solution was stirred at rt for 30min. After that time NaN₃ (0.420 g, 6.45 mmol) was added and thereaction mixture was stirred at rt for 16 h. Water was added to form aprecipitate. The precipitate was collected by filtration, and filtratewas extracted with EtOAc, which was then washed with brine, dried overMgSO₄, filtered and concentrated to give a crude solid. The combinedsolid residue was purified by normal phase chromatography to afford4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-6-methoxypyrimidine (0.59 g, 95%yield) as an off-white solid. MS(ESI) m/z: 289.08 (M+H)⁺. ¹H NMR (400MHz, CDCl₃) δ 8.76 (s, 1H), 8.62 (d, J=0.9 Hz, 1H), 7.74 (d, J=2.2 Hz,1H), 7.66 (dd, J=8.5, 2.3 Hz, 1H), 7.52 (d, J=8.4 Hz, 1H), 6.65 (d,J=1.1 Hz, 1H), 3.99 (s, 3H).

20B. Preparation of6-[5-chloro-2-(1H-1,2,3,4-tetrazol-1-yl)phenyl]pyrimidin-4-ol

To a solution of4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-6-methoxypyrimidine (0.59 g,2.044 mmol), NaI (3.06 g, 20.44 mmol) in ACN (20.44 ml) was added TMSCl(2.6 ml, 20.44 mmol), and the reaction was stirred at rt for 16 h.CELITE® was added to the reaction mixture, the slurry was filtered, andconcentrated to give a crude solid mixture. The solid was purified bynormal phase chromatography, then recrystallized from EtOAc to give6-[5-chloro-2-(1H-1,2,3,4-tetrazol-1-yl)phenyl]pyrimidin-4-ol (370 mg,66% yield) as a white solid. MS(ESI) m/z: 275.08 (M+H)⁺. ¹H NMR (400MHz, DMSO-d₆) δ 12.62 (br. s., 1H), 9.72 (s, 1H), 7.97 (d, J=0.7 Hz,1H), 7.92 (d, J=2.2 Hz, 1H), 7.87-7.83 (m, 1H), 7.82-7.78 (m, 1H), 6.48(d, J=0.7 Hz, 1H).

Intermediate 21 Preparation of6-(3-chloro-6-(4-(difluoromethyl)-1H-1,2,3-triazol-1-yl)-2-fluorophenyl)pyrimidin-4-ol

21A. Preparation of(1-(4-chloro-3-fluoro-2-(6-methoxypyrimidin-4-yl)phenyl)-1H-1,2,3-triazol-4-yl)methanol

To a cooled (0° C.), clear, yellow solution of4-chloro-3-fluoro-2-(6-methoxypyrimidin-4-yl)aniline (1.058 g, 4.17mmol) in ACN (59.6 ml) was added isoamylnitrite (0.84 ml, 6.26 mmol),followed by the dropwise addition of TMSN₃ (0.82 ml, 6.26 mmol). After10 min, the cold bath was removed, and the reaction was allowed to warmto rt. Propargyl alcohol (0.75 ml, 12.51 mmol) and Cu₂O (0.060 g, 0.42mmol) were added. After 1 h, the reaction was diluted with EtOAc andwashed with sat NH₄Cl, brine, dried over MgSO₄, filtered andconcentrated to give a brown oil. The crude product was purified bynormal phase chromatography to give(1-(4-chloro-3-fluoro-2-(6-methoxypyrimidin-4-yl)phenyl)-1H-1,2,3-triazol-4-yl)methanol(0.8 g, 57.1% yield) as a yellow foam. MS(ESI) m/z: 336.1 (M+H)⁺. ¹H NMR(400 MHz, CDCl₃) δ 8.65 (d, J=1.1 Hz, 1H), 7.69-7.62 (m, 2H), 7.37 (dd,J=8.6, 1.5 Hz, 1H), 6.81 (t, J=1.2 Hz, 1H), 4.76 (d, J=5.9 Hz, 2H), 4.00(s, 3H), 2.18 (t, J=6.1 Hz, 1H).

21B. Preparation of1-(4-chloro-3-fluoro-2-(6-methoxypyrimidin-4-yl)phenyl)-1H-1,2,3-triazole-4-carbaldehyde

To the solution of(1-(4-chloro-3-fluoro-2-(6-methoxypyrimidin-4-yl)phenyl)-1H-1,2,3-triazol-4-yl)methanol(0.8 g, 2.38 mmol) in DMSO (9.53 ml) was added IBX (0.734 g, 2.62 mmol),and the reaction was stirred at rt. After 18 h, water and sat NaHCO₃were added and the reaction mixture was extracted with EtOAc (2×). Theorganic layers were combined and dried over Na₂SO₄, filtered, andconcentrated. Purification by normal phase chromatography afforded1-(4-chloro-3-fluoro-2-(6-methoxypyrimidin-4-yl)phenyl)-1H-1,2,3-triazole-4-carbaldehyde(0.64 g, 80% yield) as a white solid. MS(ESI) m/z: 334.4 (M+H)⁺. ¹H NMR(400 MHz, CDCl₃) δ 10.12 (s, 1H), 8.60 (d, J=1.1 Hz, 1H), 8.25 (s, 1H),7.71 (dd, J=8.6, 7.5 Hz, 1H), 7.39 (dd, J=8.6, 1.8 Hz, 1H), 6.88 (dd,J=1.8, 1.1 Hz, 1H), 4.01 (s, 3H).

21C. Preparation of4-(3-chloro-6-(4-(difluoromethyl)-1H-1,2,3-triazol-1-yl)-2-fluorophenyl)-6-methoxypyrimidine

To the solution of1-(4-chloro-3-fluoro-2-(6-methoxypyrimidin-4-yl)phenyl)-1H-1,2,3-triazole-4-carbaldehyde(0.3 g, 0.9 mmol) in DCM (24 ml) was added DAST (0.54 ml, 4.09 mmol).The reaction was stirred at rt for 22 h. To the reaction was added waterand the resulting mixture was extracted with DCM. The organic layer waswashed with brine, dried over Na₂SO₄, filtered, and concentrated.Purification by normal phase chromatography afforded4-(3-chloro-6-(4-(difluoromethyl)-1H-1,2,3-triazol-1-yl)-2-fluorophenyl)-6-methoxypyrimidine(0.256 g, 80% yield) as a white solid. MS(ESI) m/z: 356.1 (M+H)⁺. ¹H NMR(400 MHz, CDCl₃) δ 8.62 (d, J=0.9 Hz, 1H), 7.94 (t, J=1.3 Hz, 1H), 7.69(dd, J=8.6, 7.5 Hz, 1H), 7.39 (dd, J=8.6, 1.8 Hz, 1H), 7.00-6.69 (m,2H), 4.00 (s, 3H).

21D. Preparation of6-(3-chloro-6-(4-(difluoromethyl)-1H-1,2,3-triazol-1-yl)-2-fluorophenyl)pyrimidin-4-ol

A clear, yellow solution of4-(3-chloro-6-(4-(difluoromethyl)-1H-1,2,3-triazol-1-yl)-2-fluorophenyl)-6-methoxypyrimidine(0.256 g, 0.72 mmol) in HOAc (3.6 ml) and 48% aq HBr (4.07 ml, 36.0mmol) was warmed to 65° C. for 3 h, and then the reaction was cooled tort and concentrated. The yellow gum was suspended in EtOAc and washedwith sat NaHCO₃ (2×), brine, dried over Na₂SO₄, filtered, andconcentrated. The residue was suspended in Et₂O (3 ml), sonicated, andfiltered. The solid was rinsed with Et₂O (2 ml), air-dried with suctionto afford6-(3-chloro-6-(4-(difluoromethyl)-1H-1,2,3-triazol-1-yl)-2-fluorophenyl)pyrimidin-4-ol(0.23 g, 94% yield) as a yellow solid. MS(ESI) m/z: 342.0 (M+H)⁺. ¹H NMR(400 MHz, CD₃OD) δ 8.56 (t, J=1.4 Hz, 1H), 8.05 (d, J=0.9 Hz, 1H), 7.86(dd, J=8.6, 7.7 Hz, 1H), 7.57 (dd, J=8.7, 1.7 Hz, 1H), 6.98 (t, J=54.0Hz, 1H), 6.58 (t, J=1.2 Hz, 1H). ¹⁹F NMR (376 MHz, CD₃OD) δ −114.68 (s),−115.20 (s).

Intermediate 22 Preparation of6-(5-chloro-1-methyl-1H-indazol-7-yl)pyrimidin-4-ol

22A. Preparation of 7-bromo-5-chloro-1-methyl-1H-indazole

To a solution of 7-bromo-5-chloro-1H-indazole (5.0 g, 21.60 mmol) andK₂CO₃ (14.93 g, 108 mmol) in DMSO (24.91 ml) was added CH₃I (1.62 ml,25.9 mmol) at rt. The reaction mixture was stirred at rt overnight.Reaction was diluted with water and the resulting solid filtered througha Buchner funnel, washed with water, and dried under vacuum. Theregioisomers were separate by normal phase chromatography eluting with agradient of hexanes/EtOAc with the 1st isomer to elute off of the columnbeing 7-bromo-5-chloro-1-methyl-1H-indazole (2.83 g, 53.4%) as confirmedby ¹H NMR and a negative NOE. MS(ESI) m/z: 245 (M+H)⁺ and 247 (M+2+H)⁺.¹H NMR (400 MHz, DMSO-d₆) δ 8.12-8.09 (m, 1H), 7.88 (d, J=1.8 Hz, 1H),7.67 (d, J=1.5 Hz, 1H), 4.32 (s, 3H).

22B. Preparation of5-chloro-1-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole

To a stirring solution of 7-bromo-5-chloro-1-methyl-1H-indazole (1.0 g,4.07 mmol) in dioxane (20.37 ml) at rt was added4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (1.190 g,4.68 mmol) and KOAc (1.839 g, 18.74 mmol). The reaction was purged withAr (3×). Pd(dppf)Cl₂ DCM complex (0.266 g, 0.326 mmol) was added, thereaction was again purged with Ar, and heated to 90° C. After stirringovernight, the reaction mixture was cooled to rt, diluted with water,extracted with EtOAc (3×), washed with water, brine, dried over Na₂SO₄,filtered, and concentrated. The crude residue was purified by normalphase column chromatography eluting with a gradient of hexanes/EtOAc togive5-chloro-1-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole(0.47 g, 39.4% yield) an oil which slowly solidified upon standing.MS(ESI) m/z: 293.0 (M+H)⁺ and 295.0 (M+2+H)⁺. ¹H NMR (400 MHz, CD₃OD) δ7.94 (s, 1H), 7.80 (d, J=2.2 Hz, 1H), 7.71 (d, J=2.2 Hz, 1H), 4.23 (s,3H), 1.40 (s, 12H).

22C. Preparation of5-chloro-7-(6-methoxypyrimidin-4-yl)-1-methyl-1H-indazole

To a large microwave vial was added 4-chloro-6-methoxypyrimidine (0.201g, 1.391 mmol),5-chloro-1-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole(0.407 g, 1.391 mmol), and 2 M aqNa₂CO₃ (0.70 ml, 1.391 mmol) in DME(5.56 ml)/EtOH (0.696 ml). The mixture was purged with Ar for severalmin, PdCl₂(dppf)-CH₂Cl₂ adduct (0.114 g, 0.139 mmol) added and thenheated at 90° C. After 4 h, the reaction mixture was cooled to rt,diluted with water, and extracted with EtOAc. The organic layer washedwith brine, dried over Na₂SO₄, filtered, and concentrated to give anorange-brown residue. The crude material was purified by normal phasecolumn chromatography eluting with a gradient of hexanes/EtOAc to give5-chloro-7-(6-methoxypyrimidin-4-yl)-1-methyl-1H-indazole (0.382, 100%)as a solid. MS(ESI) m/z: 275.1 (M+H)⁺ and 277.1 (M+2+H)⁺.

22D. Preparation of 6-(5-chloro-1-methyl-1H-indazol-7-yl)pyrimidin-4-ol

A clear, yellow solution of5-chloro-7-(6-methoxypyrimidin-4-yl)-1-methyl-1H-indazole (0.382 g,1.391 mmol) in AcOH (3 ml) and 48% aq HBr (1.639 ml, 14.49 mmol) waswarmed to 85° C. After 3 h, the reaction mixture was concentrated. Theresidue was dissolved in EtOAc and washed with sat NaHCO₃. The aqueouslayer was extracted with additional EtOAc, washed with brine, dried overNa₂SO₄, filtered, and concentrated. The resulting solid was suspendedwith Et₂O, filtered, and dried under vacuum to give6-(5-chloro-1-methyl-1H-indazol-7-yl)pyrimidin-4-ol (0.085 g, 23.5%) asa white solid. MS(ESI) m/z: 261.0 (M+H)⁺ and 263.0 (M+2+H)⁺. ¹H NMR (400MHz, DMSO-d₆) δ 12.78 (br. s., 1H), 8.32 (s, 1H), 8.13 (s, 1H), 7.97 (d,J=1.8 Hz, 1H), 7.46-7.36 (m, 1H), 6.66 (s, 1H), 3.87 (s, 3H).

Intermediate 23 Preparation of tert-butylN-[(1S)-1-(4-chloropyridin-2-yl)but-3-en-1-yl]carbamate

23A. Preparation of4-chloro-2-[(E)-2-[(S)-2-methylpropane-2-sulfinyl]ethenyl]pyridine

To a solution of S-(−)-t-butyl-sulfinamide (0.856 g, 7.06 mmol) in DCM(14.13 mL) was added sequentially CuSO₄ (2.481 g, 15.54 mmol) and4-chloropicolinaldehyde (1.0 g, 7.06 mmol). The white suspension wasstirred at rt. After 3 h, the brown suspension was filtered throughCELITE®, eluting with DCM, to give a clear brown filtrate. Concentrationgave crude product as a brown oil weighing 1.85 g. Purification bynormal phase chromatography gave tert-butylN-[(1S)-1-(4-chloropyridin-2-yl)but-3-en-1-yl]carbamate (1.31 g) as aclear, yellow oil. MS(ESI) m/z: 245.0 (M+H)⁺.

23B. Preparation of(R)—N-[(1S)-1-(4-chloropyridin-2-yl)but-3-en-1-yl]-2-methylpropane-2-sulfinamide

To a cooled (0-5° C.) mixture of InCl₃ (13.56 g, 61.3 mmol) in THF (170mL) was added dropwise over 30 min 1 M allylmagnesium bromide in Et₂O(62 mL, 61.3 mmol). The reaction was allowed to warm to rt. After 1 h, asolution of4-chloro-2-[(E)-2-[(S)-2-methylpropane-2-sulfinyl]ethenyl]pyridine (10g, 40.9 mmol) in EtOH (170 mL) was added to the reaction mixture. After2-3 h, the reaction was concentrated under vacuum at 50-55° C. The crudematerial was partitioned between EtOAc (200 ml) and water (50 ml) andthe layers were separated. The aqueous layer was extracted with EtOAc(2×50 ml). The organic layers were combined and washed with brine (100ml), dried over Na₂SO₄, filtered and concentrated to give(R)—N-[(1S)-1-(4-chloropyridin-2-yl)but-3-en-1-yl]-2-methylpropane-2-sulfinamide(13.5 g, 106%) as a yellow oil. MS(ESI) m/z: 287.2 (M+H)⁺.

23C. Preparation of (1S)-1-(4-chloropyridin-2-yl)but-3-en-1-amine

(R)—N-[(1S)-1-(4-Chloropyridin-2-yl)but-3-en-1-yl]-2-methylpropane-2-sulfinamide(75 g, 261 mmol) was dissolved in MeOH (1500 mL). 6 N HCl (750 ml, 4.5mol) was added. The reaction was stirred at rt for 2-3 h and then wasconcentrated. The residue was diluted with water (2 L), washed withEtOAc (500 ml). The aqueous layer was basified with sat aq Na₂CO₃, thenextracted into EtOAc (3×1 L). The combined organic layers were washedwith water (1 L) and brine (1 L), dried over Na₂SO₄, filtered and conc.under vacuum at 50-55° C. to give(1S)-1-(4-chloropyridin-2-yl)but-3-en-1-amine (43 g, 90%). MS(ESI) m/z:183.2 (M+H)⁺.

23D. Preparation of tert-butylN-[(1S)-1-(4-chloropyridin-2-yl)but-3-en-1-yl]carbamate

(1S)-1-(4-Chloropyridin-2-yl)but-3-en-1-amine (42 g, 230 mmol) wasdissolved in DCM (420 mL), Et₃N (32.1 mL, 230 mmol) was added followedby dropwise addition of BOC₂O (53.4 mL, 230 mmol). The reaction wasstirred at rt for 2-3 h. The reaction was diluted with excess DCM (1 L),washed with water (500 ml) and brine (500 ml). The organic layer wasdried over Na₂SO₄, filtered, and concentrated. The crude product waspurified using silica gel chromatography to give tert-butylN-[(1S)-1-(4-chloropyridin-2-yl)but-3-en-1-yl]carbamate (61 g, 86%) as apale yellow solid. MS(ESI) m/z: 283.2 (M+H)⁺. ¹H NMR (500 MHz, CDCl₃) δ8.44 (d, 1H), 7.26-7.16 (dd, 2H), 5.69-5.61 (m, 1H), 5.59 (bs, 1H),5.07-5.03 (m, 2H), 4.76 (bs, 1H), 2.62-2.55 (m, 2H), 1.42 (s, 9H).

Intermediate 24 Preparation of tert-butylN-[(1S)-1-(3-bromophenyl)but-3-en-1-yl]carbamate

24A. Preparation of(R)—N-[(1E)-(3-bromophenyl)methylidene]-2-methylpropane-2-sulfinamide

To 3-bromobenzaldehyde (7.8 g, 42.2 mmol) was added(R)-2-methylpropane-2-sulfinamide (5.11 g, 42.2 mmol), Cs₂CO₃ (20.60 g,63.2 mmol) in DCM (211 ml) and the resulting reaction mixture wasstirred for 5 days. The reaction mixture was then partitioned with brine(50 ml) and DCM (50 ml). The aqueous layer was extracted with DCM (2×50ml). The combined organic layers were washed with brine (25 ml), dried(Na₂SO₄), filtered and concentrated. Purification by normal phasechromatography using hexanes and EtOAc as eluents gave(R)—N-[(1E)-(3-bromophenyl)methylidene]-2-methylpropane-2-sulfinamide(11.8 g, 97%) as an amber oil. ¹H NMR (400 MHz, CDCl₃) δ 8.53 (s, 1H),8.02 (t, J=1.8 Hz, 1H), 7.74 (dt, J=7.7, 1.2 Hz, 1H), 7.64 (ddd, J=8.0,2.0, 1.0 Hz, 1H), 7.36 (t, J=7.8 Hz, 1H), 1.34-1.22 (m, 9H). MS(ESI)m/z: 290 (M+H)⁺.

24B. Preparation of(R)—N-[(1S)-1-(3-bromophenyl)but-3-en-1-yl]-2-methylpropane-2-sulfinamide

To (R)—N-[(1E)-(3-bromophenyl)methylidene]-2-methylpropane-2-sulfinamide(11.8 g, 40.9 mmol) in THF (190 ml), in a 3 neck flask, cooled to 0° C.,was added allyl bromide (3.90 ml, 45.0 mmol) and In (6.58 g, 57.3 mmol).After stirred at rt for 18 h, the reaction was heated to 50° C. for 6 h,then stirred at rt for 18 h. The reaction mixture was filtered throughCELITE® and the filtrate was quenched with water (100 ml). A thick cleargelatinous material formed in the aqueous layer. The organics wereextracted with EtOAc (4×75 ml). The combined organic layer was washedwith brine, dried with MgSO₄, filtered and concentrated to give(R)—N-[(1S)-1-(3-bromophenyl)but-3-en-1-yl]-2-methylpropane-2-sulfinamideas a clear oil (9.6 g, 71%). ¹H NMR (400 MHz, CDCl₃) δ 7.48 (t, J=1.8Hz, 1H), 7.41 (dt, J=7.6, 1.6 Hz, 1H), 7.26-7.18 (m, 2H), 5.79-5.66 (m,1H), 5.23-5.16 (m, 2H), 4.46 (ddd, J=8.1, 5.6, 2.0 Hz, 1H), 3.69 (s,1H), 2.63-2.53 (m, 1H), 2.53-2.40 (m, 1H), 1.23-1.19 (m, 9H).

24C. Preparation of tert-butylN-[(1S)-1-(3-bromophenyl)but-3-en-1-yl]carbamate

To(R)—N-[(1S)-1-(3-bromophenyl)but-3-en-1-yl]-2-methylpropane-2-sulfinamide(9.6 g, 29.1 mmol) in MeOH (300 ml) was added conc. HCl (4 ml). After 3h, the reaction was concentrated and the residue was dissolved in DCM(300 ml), cooled to 0° C., and then TEA (16.20 ml, 116 mmol) and Boc₂O(6.75 ml, 29.1 mmol) in DCM (20 ml) were added. After 18 h, additionalBoc₂O (1 g) was added and the reaction was stirred 4 h. The reaction wasquenched with water (100 ml) and extracted with DCM (3×50 ml). Thecombined organic layers were washed with brine (50 ml), dried (Na₂SO₄),filtered and concentrated. Purification by normal phase chromatographyusing hexanes and EtOAc as eluents gave tert-butylN-[(1S)-1-(3-bromophenyl)but-3-en-1-yl]carbamate (7.3 g, 77%) as a whitesolid. MS(ESI) m/z: 326.08 (M+H)⁺.

Intermediate 25 Preparation ofN-[(1S)-1-(3-bromo-5-fluorophenyl)but-3-en-1-yl]carbamate

25A. Preparation of(R)—N-[(1E)-(3-bromo-5-fluorophenyl)methylidene]-2-methylpropane-2-sulfinamide

To 3-bromo-5-fluorobenzaldehyde (25 g, 123 mol) dissolved in DCM (200mL) was added (R)-2-methylpropane-2-sulfinamide (14.96 g, 123 mol) andCs₂CO₃ (40.2 g, 123 mol). The reaction mixture was stirred at rtovernight. After this time, the reaction mixture was filtered andconcentrated to give a yellow oil. The yellow oil was purified using a120 g silica gel ISCO column eluted with hexanes and EtOAc to give(R)—N-[(1E)-(3-bromo-5-fluorophenyl)methylidene]-2-methylpropane-2-sulfinamide(35 g, 93%) as a yellow oil. ¹H NMR (500 MHz, DMSO-d₆) δ 8.58-8.55 (m,1H), 8.05-7.98 (m, 1H), 7.84-7.76 (m, 2H), 1.20 (s, 9H). LCMS m/z 306.1(M+H).

25B. Preparation of(R)—N-[(1S)-1-(3-bromo-5-fluorophenyl)but-3-en-1-yl]-2-methylpropane-2-sulfinamide

N-[(1E)-(3-Bromo-5-fluorophenyl)methylidene]-2,2-dimethylpropanamide (35g, 114 mol) was dissolved in THF (500 mL) in a large 3 neck RB flask andflushed with Ar. The solution was cooled to 0° C. and In powder (18.4 g,160 mol) was added followed by dropwise addition of allylbromide (15.2g, 126 mol). The reaction was stirred at 0° C. for 2 h, then the icebath was removed and the reaction mixture was stirred at rt overnight.The reaction was quenched with water (2 L) and the gelatinous materialwas filtered through CELITE®. The filtrate was concentrated to an oilymass. The crude material was dissolved in water (2 L) and the organicswere extracted with EtOAc (4×200 mL), dried over MgSO₄, filtered andconcentrated to give an oil. The oily liquid was purified via a silicagel ISCO column and eluted with DCM/MeOH to afford(R)—N-[(1S)-1-(3-bromo-5-fluorophenyl)but-3-en-1-yl]-2-methylpropane-2-sulfinamide(34.9 g, 88% yield) as a semi solid mass. LCMS m/z 348.2 (M+H). ¹H NMR(500 MHz, DMSO-d₆) δ 7.44-7.38 (m, 2H), 7.26-7.20 (m, 1H), 5.79-5.65 (m,1H), 5.46-5.42 (m, 1H), 5.04-4.98 (m, 2H), 4.41-4.34 (m, 1H), 2.69-2.59(m, 1H), 2.49-2.43 (m, 1H), 1.09 (s, 9H).

25C. Preparation ofN-[(1S)-1-(3-bromo-5-fluorophenyl)but-3-en-1-yl]carbamate

To a cooled 0° C. solution of(R)—N-[(1S)-1-(3-bromo-5-fluorophenyl)but-3-en-1-yl]-2-methylpropane-2-sulfinamide(21.9 g, 100 mol) dissolved in MeOH (100 mL) was added conc. HCl (50 mL)dropwise and then the reaction was stirred at 0° C. for 48 h. After thistime, the reaction mixture was concentrated to give a white solid mass.The residue was dissolved in water (1 L) and the organics were extractedwith EtOAc (2×200 mL), dried over MgSO₄, filtered and concentrated to abrown oil (11.5 g). The aqueous layer was basified with NaOH and theorganics were extracted with EtOAc (2×300 mL), dried over MgSO₄,filtered and concentrated to a brown oil (18 g). The combined oils weredissolved in DCM (500 mL) and to this was added Boc₂O (22 g) followed byTEA (15 mL) and the reaction mixture was stirred at rt overnight. Thereaction mixture was concentrated and purified via a 330 g silica gelIsco column eluting with hexanes and EtOAc to give a white solid. Thewhite solid was triturated with hexanes and the precipitate wascollected by filtration to giveN-[(1S)-1-(3-bromo-5-fluorophenyl)but-3-en-1-yl]carbamate (29.5 g, 87%yield).

Intermediate 26 Preparation ofN-[(1S)-1-(5-bromopyridin-3-yl)but-3-en-1-yl]carbamate

26A. Preparation of(R)—N-[(1E)-(5-chloropyridin-3-yl)methylidene]-2-methylpropane-2-sulfinamide

5-Bromonicotinaldehyde (6.6 g, 35.9 mmol) was dissolved in DCM (200 mL).To the solution was added Cs₂CO₃ (11.68 g, 35.9 mmol) and(R)-2-methylpropane-2-sulfinamide (4.34 g, 35.9 mol) and then thereaction mixture was stirred at rt overnight. The inorganics werefiltered and the filtrate was concentrated to afford(R)—N-[(1E)-(5-chloropyridin-3-yl)methylidene]-2-methylpropane-2-sulfinamideas an oil (10.4 g, 100% yield). LCMS m/z=291.3.

26B. Preparation of(R)—N-[(1S)-1-(5-chloropyridin-3-yl)but-3-en-1-yl]-2-methylpropane-2-sulfinamide

To a solution of(R)—N-[(1E)-(5-chloropyridin-3-yl)methylidene]-2-methylpropane-2-sulfinamide(10.36 g, 35.8 mmol) in THF (150 mL) at 0° C. was added powdered In(5.76 g, 50.2 mmol) followed by allylbromide (3.72 mL, 43.0 mmol). Thereaction mixture was sealed and was stirred vigorously at 0° C. for 1 hand then warmed to rt and stirred overnight. The reaction graduallyturned from pale yellow to greenish yellow to dark greenish yellow withthe indium metal forming fine particles. LCMS of the greenish blackheterogenous solution showed the desired product peak and mass. Thesolution was filtered through a pad of CELITE® and washed with EtOAc.The solution was concentrated to afford a yellow solid mass. The solidswere dissolved in MeOH (100 mL) and a solution of 4 N HCl in dioxane (25mL) was added. The resultant solution was stirred at rt. After 6 h,conc. HCl (1 mL) was added and stirring was continued for 1 h. Thereaction mixture was concentrated to give a yellow solid. The solid wasdissolved in a mixture of THF and dioxane and DCM (1:1:1, 200 mL). Tothis solution was added TEA (20 mL) followed by Boc₂O (8.1 g, 37.1 mmol)and the reaction mixture was stirred overnight. LCMS confirmed thedesired product formation. To the reaction mixture was added water (200mL) and the mixture was filtered through a pad of CELITE® and washedwith EtOAc (200 mL). The aqueous layer was extracted with EtOAc (2×100mL). The combined organic layer was dried over MgSO₄, filtered andconcentrated to give a reddish brown oil. The crude material waspurified via a 80 g silica gel ISCO column and eluted with hexanes andEtOAc.(R)—N-[(1S)-1-(5-Chloropyridin-3-yl)but-3-en-1-yl]-2-methylpropane-2-sulfinamidewas obtained as a pale yellow semi solid mass (4.3 g, 36.7% yield). LCMSm/z 327.1 (M+H). ¹H NMR (400 MHz, CDCl₃) δ 8.61-8.59 (m, 1H), 8.51-8.48(m, 1H), 7.77-7.74 (m, 1H), 5.76-5.63 (m, 1H), 5.23-5.14 (m, 2H),5.00-4.84 (m, 1H), 4.83-4.70 (m, 1H), 2.60-2.44 (m, 2H), 1.48-1.35 (m,9H).

Intermediate 27 Preparation of tert-butylN-[(1S)-1-(2-bromopyridin-4-yl)but-3-en-1-yl]carbamate

27A. Preparation of(R)—N-[(1E)-(2-bromopyridin-4-yl)methylidene]-2-methylpropane-2-sulfinamide

To a stirred suspension of (R)-2-methylpropane-2-sulfinamide (13.03 g,108 mmol) and Cs₂CO₃ (52.5 g, 161 mmol) in DCM (400 ml) was added2-bromopyridine-4-carbaldehyde (20 g, 108 mmol) over 10 min. Thereaction mixture was then stirred for 18.5 h at rt. The reaction mixturewas concentrated and the residue was diluted with EtOAc (50 ml) andwashed with brine (3×20 ml). The organic layer was dried over MgSO₄,filtered and the filtrate concentrated. The residue was purified bynormal phase chromatography using hexanes and EtOAc as eluents to afford(R)—N-[(1E)-(2-bromopyridin-4-yl)methylidene]-2-methylpropane-2-sulfinamide(27.2 g, 87%) as a white solid. MS(ESI) m/z: 289-291.0 (M+H)⁺.

27B. Preparation of(R)—N-[(1S)-1-(2-bromopyridin-4-yl)but-3-en-1-yl]-2-methylpropane-2-sulfonamide

To a solution of(R)—N-[(1E)-(2-bromopyridin-4-yl)methylidene]-2-methylpropane-2-sulfinamide(0.73 g, 2.52 mmol) and In (0.435 g, 3.79 mmol) in THF (6 ml) was slowlyadded 3-bromoprop-1-ene (0.458 g, 3.79 mmol) and resulting solution washeated at 60° C. for 18 h. The reaction mixture was cooled, filteredthrough CELITE® and the filtrate was concentrated. To the residue wasadded EtOAc (100 ml) and 5% aq NaHCO₃ (1 L) and an emulsion formedimmediately. The suspension was filtered through paper. The organiclayer was washed with brine, dried over Na₂SO₄, filtered, andconcentrated. The residue was purified by normal phase chromatographyusing hexanes and EtOAc as eluents to afford (0.62 g, 74%) of(R)—N-[(1S)-1-(2-bromopyridin-4-yl)but-3-en-1-yl]-2-methylpropane-2-sulfonamideas a yellow liquid. MS(ESI) m/z: 331-333.0 (M+H)⁺.

27C. Preparation of tert-butylN-[(1S)-1-(2-bromopyridin-4-yl)but-3-en-1-yl]carbamate

To a solution of(R)—N-[(1S)-1-(2-bromopyridin-4-yl)but-3-en-1-yl]-2-methylpropane-2-sulfinamide(1.38 g, 4.17 mmol) in MeOH (10 ml) was added 4 N HCl in dioxane (5.21mL, 20.83 mmol). The reaction mixture was stirred for 1.5 h at rt, thenwas concentrated. To the resulting residue was added ACN (10 ml), TEA(5.8 ml, 41.7 mmol) and Boc₂O (1.818 g, 8.33 mmol). After 18 h, thereaction mixture was concentrated and the residue was taken up in EtOAc,washed with water, brine, dried over MgSO₄, filtered and concentrated.The resulting residue was purified by normal phase chromatography usinghexanes and EtOAc as eluents to afford tert-butylN-[(1S)-1-(2-bromopyridin-4-yl)but-3-en-1-yl]carbamate (0.80 g, 58.7%)as a pale yellow oil. MS(ESI) m/z: 324-326.1 (M+H)⁺.

Intermediate 28 Preparation of(9R,13S)-13-amino-3,9-dimethyl-3,4,7,18-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

28A. Preparation of(S)—N-[(1E)-(6-chloropyridin-2-yl)methylidene]-2-methylpropane-2-sulfinamide

To a solution of (S)-2-methylpropane-2-sulfinamide (1.712 g, 14.13 mmol)in DCM (61.4 mL) was added Cs₂CO₃ (6.91 g, 21.19 mmol) and6-chloropicolinaldehyde (2.0 g, 14.13 mmol). The resulting whitesuspension was stirred at rt. After 17 h, the reaction was filtered. Thefiltrate was diluted with EtOAc (100 ml) and washed with brine (3×50mL). The organic layer was dried over MgSO₄, filtered and concentratedto give(S)—N-[(1E)-(6-chloropyridin-2-yl)methylidene]-2-methylpropane-2-sulfinamide(3.58 g, 100%) as a yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 8.65 (s, 1H),7.99-7.94 (m, 1H), 7.79 (t, J=7.7 Hz, 1H), 7.45 (dd, J=7.9, 0.7 Hz, 1H),1.28 (s, 10H).

28B. Preparation of(S)—N-[(1S)-1-(6-chloropyridin-2-yl)but-3-en-1-yl]-2-methylpropane-2-sulfinamide,and 28C. Preparation of(S)—N-[(1R)-1-(6-chloropyridin-2-yl)but-3-en-1-yl]-2-methylpropane-2-sulfinamide

To a mixture of(S)—N-[(1E)-(6-chloropyridin-2-yl)methylidene]-2-methylpropane-2-sulfinamide(1.73 g, 7.07 mmol) and In (0.92 g, 10.60 mmol) in THF (17.7 ml) wasslowly added 3-bromoprop-1-ene (0.92 g, 10.60 mmol). The reaction washeated at 60° C. overnight. The reaction mixture was cooled to rt,filtered through CELITE® and the filtrate was concentrated. Theresulting residue was purified by normal phase chromatography, usinghexanes and EtOAc, which gave a 5.6:1 of(S)—N-[(1S)-1-(6-chloropyridin-2-yl)but-3-en-1-yl]-2-methylpropane-2-sulfinamide:(S)—N-[(1R)-1-(6-chloropyridin-2-yl)but-3-en-1-yl]-2-methylpropane-2-sulfinamide(2.42 g, 58%) as a brown semi-solid. MS(ESI) m/z: 287.4 (M+H)⁺.

28D. Preparation of(S)-2-methyl-N-[(1R)-1-[6-(1-methyl-4-nitro-1H-pyrazol-5-yl)pyridin-2-yl]but-3-en-1-yl]propane-2-sulfinamide(Diastereomer A), and 28E. Preparation of(S)-2-methyl-N-[(1S)-1-[6-(1-methyl-4-nitro-1H-pyrazol-5-yl)pyridin-2-yl]but-3-en-1-yl]propane-2-sulfinamide(Diastereomer B)

To a N₂ flushed pressure vial was added 5.6:1 of(S)—N-[(1S)-1-(6-chloropyridin-2-yl)but-3-en-1-yl]-2-methylpropane-2-sulfinamide:(S)—N-[(1R)-1-(6-chloropyridin-2-yl)but-3-en-1-yl]-2-methylpropane-2-sulfinamide(2.18 g, 7.60 mmol), 1-methyl-4-nitro-1H-pyrazole (0.966 g, 7.60 mmol),prepared as described in Intermediate 32A,di(adamant-1-yl)(butyl)phosphine (0.954 g, 2.66 mmol), PvOH (0.300 ml,2.58 mmol), K₂CO₃ (3.62 g, 26.2 mmol), Pd(OAc)₂ (0.341 g, 1.52 mmol) andDMF (15.2 mL). The vial was purged with Ar. The vial was sealed andheated at 120° C. overnight. The reaction mixture was cooled to rt,partitioned between water and EtOAc, and the layers were separated. Theaqueous layer was extracted with EtOAc (3×) and the organic layers werecombined and concentrated. The crude product was purified using normalphase chromatography followed a second purification by reverse phasechromatography to give(S)-2-methyl-N-[(1R)-1-[6-(1-methyl-4-nitro-1H-pyrazol-5-yl)pyridin-2-yl]but-3-en-1-yl]propane-2-sulfinamide(Diastereomer A) (0.275 g, 13%), MS(ESI) m/z: 274.4 (M+H)⁺; and(S)-2-methyl-N-[(1S)-1-[6-(1-methyl-4-nitro-1H-pyrazol-5-yl)pyridin-2-yl]but-3-en-1-yl]propane-2-sulfinamide(Diastereomer B) (1.2 g, 57%); MS(ESI) m/z: 274.4 (M+H)⁺.

28F. Preparation of tert-butylN-[(1S)-1-[6-(1-methyl-4-nitro-1H-pyrazol-5-yl)pyridin-2-yl]but-3-en-1-yl]carbamate

(1S)-1-(6-(1-Methyl-4-nitro-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-amine(Diastereomer B) (1.2 g, 3.18 mmol) was dissolved in MeOH (5 mL) anddioxane (25 ml). 4 N HCl in dioxane (4.8 ml, 19.1 mmol) was added. Thereaction was stirred at rt for 3 h and then was concentrated. Theresidue was coevaporated with toluene, dissolved in DCM (40 mL), andcooled to 0° C. TEA (4.43 mL, 31.8 mmol) was added followed by BOC₂O(0.738 mL, 3.18 mmol). The reaction was stirred at 0° C. for 15 min andthen the reaction was allowed to warm to rt. After 2 h, the reaction wasdiluted with DCM, washed with sat NaHCO₃, brine, and concentrated.Purification by normal phase chromatography gave tert-butylN-[(1S)-1-[6-(1-methyl-4-nitro-1H-pyrazol-5-yl)pyridin-2-yl]but-3-en-1-yl]carbamate(393 mg, 33% yield) as an orange oil. MS(ESI) m/z: 374.5 (M+H)⁺. ¹H NMR(400 MHz, CDCl₃) δ 8.19 (s, 1H), 7.84 (t, J=7.8 Hz, 1H), 7.55 (d, J=7.7Hz, 1H), 7.38 (d, J=7.7 Hz, 1H), 5.77-5.58 (m, 1H), 5.40 (br. s., 1H),5.13-5.01 (m, 2H), 4.92 (d, J=6.8 Hz, 1H), 3.86 (s, 3H), 2.71-2.51 (m,2H), 1.43 (s, 9H).

28G. Preparation of tert-butylN-[(1S)-1-[6-(4-amino-1-methyl-1H-pyrazol-5-yl)pyridin-2-yl]but-3-en-1-yl]carbamate

To a solution of tert-butylN-[(1S)-1-[6-(1-methyl-4-nitro-1H-pyrazol-5-yl)pyridin-2-yl]but-3-en-1-yl]carbamate (393 mg, 1.05 mmol) in MeOH (6.4mL) was added AcOH (0.64 mL). The reaction mixture was heated to 45° C.then Zn powder (206 mg, 3.16 mmol) was added portionwise. After 1 h,additional Zn (198 mg) was added. Upon completion of the reaction, themixture was cooled to rt, partitioned between DCM and sat NaHCO₃, andthe layers were separated. The aqueous layer was extracted with DCM(2×). The organic layers were combined and washed with brine, dried overMgSO₄, filtered and concentrated to give tert-butylN-[(1S)-1-[6-(4-amino-1-methyl-1H-pyrazol-5-yl)pyridin-2-yl]but-3-en-1-yl]carbamate(343 mg, 95% yield) as a yellow foam. MS(ESI) m/z: 344.5 (M+H)⁺. ¹H NMR(400 MHz, CDCl₃) δ 7.74 (t, J=7.8 Hz, 1H), 7.39 (dd, J=7.8, 0.8 Hz, 1H),7.25-7.18 (m, 1H), 7.14 (d, J=7.7 Hz, 1H), 5.70 (ddt, J=17.1, 10.2, 7.0Hz, 1H), 5.46 (d, J=6.8 Hz, 1H), 5.13-4.99 (m, 2H), 4.89 (d, J=6.8 Hz,1H), 4.01 (s, 3H), 2.71-2.53 (m, 2H), 1.49-1.30 (m, 9H).

28H. Preparation of tert-butylN-[(1S)-1-(6-{1-methyl-4-[(2R)-2-methylbut-3-enamido]-1H-pyrazol-5-yl}pyridin-2-yl)but-3-en-1-yl]carbamate

To tert-butyl N-[(1S)-1-[6-(4-amino-1-methyl-1H-pyrazol-5-yl)pyridin-2-yl]but-3-en-1-yl]carbamate (343 mg, 0.999 mmol) in EtOAc (3.33ml) was added a solution of (R)-2-methylbut-3-enoic acid (0.150 g, 1.498mmol), prepared as described in Intermediate 2, in EtOAc (1 ml). Themixture was cooled to 0° C. and pyridine (0.24 ml, 3.0 mmol) was added,followed by the addition of a solution of 50% T3P® in EtOAc (1.19 ml,1.50 mmol). After 2 h, the reaction was partitioned between sat NaHCO₃and EtOAc, and the layers were separated. The aqueous layer wasextracted with EtOAc (2×). The organic layers were combined and washedwith brine and then concentrated. Purification by normal phasechromatography gave tert-butylN-[(1S)-1-(6-{1-methyl-4-[(2R)-2-methylbut-3-enamido]-1H-pyrazol-5-yl)}pyridin-2-yl)but-3-en-1-yl]carbamate (360 mg, 85%) as a yellow solid. MS(ESI) m/z:426.5 (M+H)⁺. ¹H NMR (400 MHz, CDCl₃) δ 9.35 (br. s., 1H), 8.30 (s, 1H),7.82 (t, J=7.8 Hz, 1H), 7.40 (d, J=7.9 Hz, 1H), 7.32-7.19 (m, 1H), 6.01(ddd, J=17.4, 10.0, 7.6 Hz, 1H), 5.78-5.57 (m, 1H), 5.35-5.04 (m, 5H),4.91 (br. s., 1H), 4.06 (s, 3H), 3.26-3.06 (m, 1H), 2.81-2.54 (m, 2H),1.54-1.30 (m, 12H).

28I. Preparation of tert-butylN-[(9R,10E,13S)-3,9-dimethyl-8-oxo-3,4,7,18-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate

A solution of tert-butylN-[(1S)-1-(6-{1-methyl-4-[(2R)-2-methylbut-3-enamido]-1H-pyrazol-5-yl}pyridin-2-yl)but-3-en-1-yl]carbamate (140 mg, 0.329 mmol) in EtOAc (25 ml) was purgedwith Ar for 20 min. Second Generation Grubbs Catalyst (0.112 g, 0.132mmol) was added and the reaction mixture was heated at 80° C. overnight.The reaction mixture was cooled to rt and concentrated. Purification bynormal phase chromatography and then by reverse phase chromatography wasdone. The fractions containing the desired product were made basic(pH˜8) with sat NaHCO₃ and then concentrated. The residue waspartitioned between water and EtOAc, and the layers were separated. Theaqueous layer was extracted with DCM (3×) and EtOAc (3×). The organiclayers were combined and washed with brine, dried MgSO₄, filtered andconcentrated to give tert-butylN-[(9R,10E,13S)-3,9-dimethyl-8-oxo-3,4,7,18-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate(96 mg, 66% yield). MS(ESI) m/z: 398.2 (M+H)⁺. ¹H NMR (400 MHz, CDCl₃) δ11.12 (br. s., 1H), 8.08 (s, 1H), 7.84 (t, J=7.9 Hz, 1H), 7.39 (dd,J=7.9, 0.7 Hz, 1H), 7.32-7.24 (m, 1H), 5.98-5.83 (m, 1H), 5.55 (dd,J=15.7, 7.4 Hz, 1H), 5.41 (d, J=6.6 Hz, 1H), 5.04 (m, 1H), 4.10-4.03 (m,3H), 3.15 (quin, J=7.3 Hz, 1H), 2.84-2.56 (m, 2H), 1.51-1.32 (m, 12H).

28J. Preparation of tert-butylN-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,18-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate,and 28K. Preparation of tert-butylN-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,18-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-2(6),4-dien-13-yl]carbamate

A solution of tert-butylN-[(9R,10E,13S)-3,9-dimethyl-8-oxo-3,4,7,18-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate(0.096 g, 0.024 mmol) in EtOH (4 ml) was hydrogenated at 20 psi H₂ inthe presence of PtO₂ (20 mg) for 20 h. The mixture was filtered, washingwith MeOH and EtOAc. The filtrate was concentrated and then purified byreverse phase chromatography to give, following neutralization of thefractions and extraction, tert-butylN-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,18-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-2(6),4-dien-13-yl]carbamate(20 mg, 20.4% yield), MS(ESI) m/z: 406.2 (M+H)⁺; and tert-butylN-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,18-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate(68 mg, 70.5% yield), MS(ESI) m/z: 400.2 (M+H)⁺.

28L. Preparation of(9R,13S)-13-amino-3,9-dimethyl-3,4,7,18-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

To a solution of tert-butylN-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,18-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate(0.035 g, 0.088 mmol) in DCM (0.5 ml) was added TFA (0.2 mL, 2.60 mmol).After stirring for 1 h, the reaction mixture was concentrated todryness, and coevaporated with CH₃CN. The residue was neutralized bydissolving in MeOH, passing through NaHCO₃ cartridge (StratoSpheres SPE;500 mg, 0.90 mmol loading), and the filtrate concentrated to give(9R,13S)-13-amino-3,9-dimethyl-3,4,7,18-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(15 mg, 57% yield) as clear glass. MS(ESI) m/z: 300.5 (M+H)⁺.

Intermediate 29 Preparation of(9R,13S)-13-amino-16-fluoro-3,9-dimethyl-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

29A. Preparation of tert-butylN-[(1S)-1-[3-fluoro-5-(1-methyl-4-nitro-1H-pyrazol-5-yl)phenyl]but-3-en-1-yl]carbamate

To tert-butyl N-[(1S)-1-(3-bromo-5-fluorophenyl)but-3-en-1-yl]carbamate(0.19 g, 0.552 mmol), 1-methyl-4-nitro-1H-pyrazole (0.070 g, 0.552mmol), di(adamantan-1-yl)(butyl)phosphine (0.059 g, 0.166 mmol), pivalicacid (0.019 ml, 0.166 mmol), K₂CO₃ (0.229 g, 1.656 mmol) was added DMF(1.1 ml), and the mixture was purged with Ar. Pd(OAc)₂ (0.025 g, 0.110mmol) was added and the reaction was heated at 120° C. for 18 h. Thereaction was partitioned between water (15 ml) and EtOAc (30 ml). Theaqueous layer was extracted with EtOAc (2×20 ml). The combined organiclayers was washed with brine (15 ml), dried over MgSO₄, filtered andconcentrated. The residue was purified by normal phase chromatographyusing hexanes and EtOAc as eluents to give tert-butylN-[(1S)-1-[3-fluoro-5-(1-methyl-4-nitro-1H-pyrazol-5-yl)phenyl]but-3-en-1-yl]carbamate(0.123 g, 57%) as a yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 8.23-8.17 (m,1H), 7.22-7.16 (m, 1H), 7.10 (s, 1H), 7.01 (dt, J=8.5, 1.9 Hz, 1H),5.76-5.60 (m, 1H), 5.22-5.11 (m, 2H), 4.90 (br. s., 1H), 4.78 (br. s.,1H), 3.78-3.69 (m, 3H), 2.60-2.48 (m, 2H), 1.41 (br. s., 9H).

29B. Preparation of tert-butylN-[(1S)-1-[3-(4-amino-1-methyl-1H-pyrazol-5-yl)-5-fluorophenyl]but-3-en-1-yl]carbamate

To tert-butylN-[(1S)-1-[3-fluoro-5-(1-methyl-4-nitro-1H-pyrazol-5-yl)phenyl]but-3-en-1-yl]carbamate(0.123 g, 0.315 mmol) dissolved in acetone (5 ml)/water (1 ml), cooledto 0° C., and NH₄Cl (0.084 g, 1.575 mmol) and Zn (0.206 g, 3.15 mmol)were added. The ice bath was removed. After 3 h, the reaction wasfiltered and filtrate was partitioned between water (10 ml) and EtOAc(30 ml). The aqueous layer was extracted with EtOAc (2×20 ml). Thecombined organic layers was washed with brine (10 ml), dried over MgSO₄,filtered and concentrated. The residue was purified by normal phasechromatography using DCM and 0-10% MeOH as eluents to give tert-butylN-[(1S)-1-[3-(4-amino-1-methyl-1H-pyrazol-5-yl)-5-fluorophenyl]but-3-en-1-yl]carbamate(0.105 g, 92%). MS(ESI) m/z: 361.08 (M+H)⁺.

29C. Preparation of tert-butylN-[(1S)-1-(3-fluoro-5-{1-methyl-4-[(2R)-2-methylbut-3-enamido]-1H-pyrazol-5-yl}phenyl)but-3-en-1-yl]carbamate

To tert-butylN-[(1S)-1-[3-(4-amino-1-methyl-1H-pyrazol-5-yl)-5-fluorophenyl]but-3-en-1-yl]carbamate(0.105 g, 0.291 mmol) in EtOAc (0.58 ml) was added(R)-2-methylbut-3-enoic acid (0.035 g, 0.350 mmol), prepared asdescribed in Intermediate 2, in 0.3 ml EtOAc. The mixture was cooled to0° C. and Hunig's Base (0.153 ml, 0.874 mmol) followed by a solution of50% T3P® in EtOAc (0.347 ml, 0.583 mmol) were added. After 4 h, thereaction was partitioned with sat NaHCO₃ (5 ml) and EtOAc (5 ml). Theaqueous layer was extracted with EtOAc (2×10 ml). The combined organiclayers was washed with brine (5 ml), dried over MgSO₄, filtered andconcentrated. The residue was purified by normal phase chromatographyusing hexanes and EtOAc as eluents to give the desired product (53.0 mg,41%) as a yellow foam. MS(ESI) m/z: 443.5 (M+H)⁺.

29D. Preparation of tert-butylN-[(9R,10E,13S)-16-fluoro-3,9-dimethyl-8-oxo-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate

A solution of tert-butylN-[(1S)-1-(3-fluoro-5-{1-methyl-4-[(2R)-2-methylbut-3-enamido]-1H-pyrazol-5-yl}phenyl)but-3-en-1-yl]carbamate(0.053 g, 0.120 mmol) in degassed DCE (10 ml) was heated to 120° C. for30 min in a microwave in the presence of Second Generation GrubbsCatalyst (0.041 g, 0.048 mmol). The reaction mixture was directlypurified by normal phase chromatography using hexanes and EtOAc aseluents to give tert-butylN-[(9R,10E,13S)-16-fluoro-3,9-dimethyl-8-oxo-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate(27.0 mg, 54%) as a dark solid. MS(ESI) m/z: 415.4 (M+H)⁺.

29E. Preparation of(9R,13S)-13-amino-16-fluoro-3,9-dimethyl-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

A solution of tert-butylN-[(9R,10E,13S)-16-fluoro-3,9-dimethyl-8-oxo-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate(0.027 g, 0.065 mmol) in EtOH (3 ml) was hydrogenated in the presence ofPtO₂ (5 mg) for 6 h. After this time, the reaction was filtered throughCELITE® and the filtrate was concentrated to tert-butylN-[(9R,13S)-16-fluoro-3,9-dimethyl-8-oxo-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate(19 mg). The Boc protecting group was removed by dissolving the materialin 3 ml of 50% TFA/DCM. After 2 h, the reaction mixture was concentratedand the residue was taken up in DCM and MeOH, and filtered through abasic cartridge. Concentration of the filtrate afforded(9R,13S)-13-amino-16-fluoro-3,9-dimethyl-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(19 mg, 92%) as a dark solid. MS(ESI) m/z: 317.4 (M+H)⁺.

Intermediate 30 Preparation of(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

30A. Preparation of 1-(difluoromethyl)-4-nitro-1H-pyrazole

Cs₂CO₃ (14.41 g, 44.2 mmol) was suspended in a solution of4-nitro-1H-pyrazole (5.00 g, 44.2 mmol) and DMF (40 mL). After heatingto 120° C. for 5 min, solid sodium 2-chloro-2,2-difluoroacetate (13.48g, 88 mmol) was added in 10 equal portions over 20 min. The reaction wascomplete after 10 min of additional heating. The mixture was added to aseparatory funnel containing 100 mL water and extracted with Et₂O (2×50mL). The combined organic layers were concentrated. Purification bynormal-phase chromatography eluting with a gradient of hexanes/EtOAcyielded 1-(difluoromethyl)-4-nitro-1H-pyrazole (6.99 g, 42.9 mmol, 97%yield) as a clear, colorless oil. ¹H NMR (500 MHz, CDCl₃) δ 8.58 (s,1H), 8.22 (s, 1H), 7.39-7.05 (t, J=60 Hz, 1H).

30B. Preparation of (S)-tert-butyl(1-(4-(1-(difluoromethyl)-4-nitro-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate

To a N₂ flushed, 500 mL RBF was added (S)-tert-butyl(1-(4-chloropyridin-2-yl)but-3-en-1-yl)carbamate, prepared as describedin Intermediate 23, (10 g, 35.4 mmol),1-(difluoromethyl)-4-nitro-1H-pyrazole, prepared as described inIntermediate 30A, (6.34 g, 38.9 mmol) and dioxane (100 mL). The solutionwas bubbled with N₂ for 5 min and Pd(OAc)₂ (0.40 g, 1.7 mmol),di(adamantan-1-yl)(butyl)phosphine (1.27 g, 3.5 mmol), K₂CO₃ (14.7 g,106 mmol) and PvOH (1.08 g, 10.61 mmol) were added. The reaction mixturewas bubbled with N₂ for 5 min, then heated to 100° C. for 3 h. Water(200 mL) was added. The reaction mixture was then extracted with EtOAc(2×200 mL). The combined organic extracts were washed with water (200mL), brine (200 mL), dried over Na₂SO₄, filtered and concentrated.Purification by normal phase chromatography eluting with a gradient ofhexanes/EtOAc afforded (S)-tert-butyl(1-(4-(1-(difluoromethyl)-4-nitro-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate(12.91 g, 31.5 mmol, 89% yield) as a yellowish oil. MS(ESI) m/z: 410.4[M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.80 (dd, J=5.1, 0.7 Hz, 1H), 8.36 (s,1H), 7.34 (s, 1H), 7.31 (dd, J=5.1, 1.5 Hz, 1H), 7.27-6.91 (t, J=58 Hz,1H), 5.79-5.63 (m, 1H), 5.16-5.03 (m, 2H), 4.92 (d, J=5.9 Hz, 1H), 2.67(t, J=6.4 Hz, 2H), 1.46 (br. s., 9H).

30C. Preparation of(S)-tert-butyl(1-(4-(4-amino-1-(difluoromethyl)-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate

To a 100 mL, 3-necked RBF was added a solution of (S)-tert-butyl(1-(4-(1-(difluoromethyl)-4-nitro-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate(0.78 g, 1.90 mmol) in MeOH (12 mL) and a solution of NH₄Cl (1.02 g, 19mmol) in water (3 mL). To the solution was added Fe (0.53 g, 9.49 mmol).The reaction mixture was heated to 65° C. for 3 h. Water (50 mL) wasadded. After cooling to rt, the mixture was filtered through a CELITE®pad and rinsed with MeOH (200 mL). The filtrate was concentrated. Theresidue was partitioned between EtOAc (100 mL) and water (100 mL). Theorganic phase was separated, washed with water (100 mL), brine (100 mL),dried over Na₂SO₄, filtered and concentrated in vacuo. Purification bynormal phase chromatography eluting with a gradient of DCM/MeOH yielded(S)-tert-butyl(1-(4-(4-amino-1-(difluoromethyl)-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate(0.585 g, 1.54 mmol, 81% yield) as an oil. MS(ESI) m/z: 380.1 [M+H]⁺. ¹HNMR (400 MHz, CDCl₃) δ 8.70 (dd, J=5.0, 0.7 Hz, 1H), 7.43 (s, 1H), 7.36(s, 1H), 7.32 (dd, J=5.1, 1.5 Hz, 1H), 7.28-6.97 (t, J=58 Hz, 1H),5.80-5.66 (m, 1H), 5.65-5.53 (m, 1H), 5.13-5.03 (m, 2H), 4.87 (br. s.,1H), 3.22 (br. s., 2H), 2.65 (t, J=6.5 Hz, 2H), 1.52-1.37 (m, 9H).

30D. Preparation of tert-butyl((S)-1-(4-(1-(difluoromethyl)-4-((R)-2-methylbut-3-enamido)-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate

To a N₂ flushed, 3-necked, 250 mL RBF was added a solution of(S)-tert-butyl(1-(4-(4-amino-1-(difluoromethyl)-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate(5 g, 13.18 mmol) and EtOAc (50 mL). The solution was cooled to −10° C.and (R)-2-methylbut-3-enoic acid, as prepared in Intermediate 2, (1.72g, 17.13 mmol), pyridine (4.26 mL, 52.7 mmol), and T3P® (23.54 mL, 39.5mmol) were added. The cooling bath was removed and the solution wasallowed to warm to rt and then stir over a period of 20 h. Water (30 mL)and EtOAc (30 mL) were added and the mixture was stirred for 30 min. Theorganic phase was separated and the aqueous layer was extracted withEtOAc (30 mL). The combined organic extracts were washed with brine (50mL), dried over Na₂SO₄, filtered and concentrated. Purification bynormal phase chromatography eluting with a gradient of hexanes/EtOAcgave tert-butyl((S)-1-(4-(1-(difluoromethyl)-4-((R)-2-methylbut-3-enamido)-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate(5.69 g, 12.33 mmol, 94% yield). MS(ESI) m/z: 462.2 [M+H]⁺. ¹H NMR (400MHz, CDCl₃) δ 8.75 (dd, J=5.0, 0.6 Hz, 1H), 8.37 (s, 1H), 7.32 (t, J=59Hz, 1H), 7.28 (br. s., 1H), 7.20 (s, 1H), 5.97-5.85 (m, 1H), 5.78-5.65(m, 1H), 5.56-5.44 (m, 1H), 5.28-5.19 (m, 2H), 5.12 (d, J=2.0 Hz, 2H),4.91-4.82 (m, 1H), 3.20-3.11 (m, 1H), 2.72-2.62 (m, 2H), 1.48-1.43 (s,9H), 1.33 (d, J=6.8 Hz, 3H).

30E. Preparation of tert-butylN-[(9R,10E,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0²,⁶]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate

To a N₂ flushed, 2 L, 3-necked, RBF was added a solution of tert-butyl((S)-1-(4-(1-(difluoromethyl)-4-((R)-2-methylbut-3-enamido)-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate(3 g, 6.50 mmol) in EtOAc (1300 mL). The solution was sparged with Arfor 15 min. Second Generation Grubbs Catalyst (1.38 g, 1.63 mmol) wasadded in one portion. The reaction mixture was heated to reflux for 24h. After cooling to rt, the solvent was removed and the residue waspurified by normal phase chromatography eluting with a gradient ofDCM/MeOH to yield tert-butylN-[(9R,10E,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0²,⁶]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate(2.13 g, 4.91 mmol, 76% yield) as a tan solid. MS(ESI) m/z: 434.4[M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.71 (d, J=5.1 Hz, 1H), 7.78 (s, 1H),7.44-7.40 (m, 1H), 7.36 (br. s., 1H), 7.27 (t, J=58 Hz, 1H), 6.87 (s,1H), 6.49-6.39 (m, 1H), 5.78 (s, 1H), 4.80 (br. s., 2H), 3.18-3.08 (m,1H), 3.08-2.98 (m, 1H), 2.06-1.93 (m, 1H), 1.51 (s, 9H), 1.19 (d, J=6.6Hz, 3H).

30F. Preparation of tert-butylN-[(9R,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate

Pd/C (0.60 g, 0.570 mmol) was added to a 250 mL Parr hydrogenation flaskcontaining a solution of tert-butylN-[(9R,10E,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0²,⁶]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate(2.46 g, 5.68 mmol) in EtOH (100 mL). The flask was purged with N₂ andpressurized to 55 psi of H₂ allowed to stir for 18 h. The reaction wasfiltered through CELITE® and concentrated to yield tert-butylN-[(9R,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate(2.17 g, 88% yield) as a tan solid. MS(ESI) m/z: 436.3 [M+H]⁺. ¹H NMR(400 MHz, DMSO-d₆) δ 9.32 (s, 1H), 8.71 (d, J=5.0 Hz, 1H), 7.96 (t, J=58Hz, 1H), 7.43 (s, 1H), 7.32 (d, J=4.8 Hz, 1H), 7.22 (d, J=7.3 Hz, 1H),4.66 (d, J=8.3 Hz, 1H), 2.62 (br. s., 1H), 1.88 (d, J=12.8 Hz, 1H),1.77-1.59 (m, 2H), 1.42-1.28 (m, 9H), 1.15 (d, J=18.2 Hz, 2H), 0.83 (d,J=7.0 Hz, 3H).

Example 30G. Preparation of(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

4 N HCl in dioxane (3.88 mL, 15.5 mmol) was added to a solution oftert-butylN-[(9R,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate(2.25 g, 5.2 mmol) in MeOH (10 mL). The reaction was allowed to stir atrt for 2 h. The reaction was cooled in an ice bath, and 7 N NH₃ in MeOH(13.3 mL, 93.0 mmol) was added. After 5 min, the reaction was dilutedwith CH₂Cl₂ (80 mL) and the solid that formed was filtered. The filtratewas concentrated to yield(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(1.3 g, 3.88 mmol, 75% yield). MS(ESI) m/z: 336.3 [M+H]⁺. ¹H NMR (400MHz, DMSO-d₆) δ 9.33 (s, 1H), 8.71 (d, J=5.0 Hz, 1H), 7.94 (t, J=58 Hz,1H), 7.85 (s, 1H), 7.40 (s, 1H), 7.32 (d, J=5.0 Hz, 1H), 4.01 (dd,J=10.2, 5.1 Hz, 1H), 2.63-2.53 (m, 1H), 1.90-1.69 (m, 2H), 1.53-1.36 (m,2H), 1.16-1.00 (m, 1H), 0.85 (d, J=7.0 Hz, 3H).

Intermediate 31 Preparation of(9R,13S)-13-amino-3,9-dimethyl-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one,hydrochloride

31A. Preparation of tert-butylN-[(1S)-1-[3-(1-methyl-4-nitro-1H-pyrazol-5-yl)phenyl]but-3-en-1-yl]carbamate

To tert-butyl N-[(1S)-1-(3-bromophenyl)but-3-en-1-yl]carbamate (2 g,6.13 mmol), 1-methyl-4-nitro-1H-pyrazole (0.779 g, 6.13 mmol),di(adamantan-1-yl)(butyl) phosphine (0.659 g, 1.839 mmol), pivalic acid(0.213 ml, 1.839 mmol), K₂CO₃ (2.54 g, 18.39 mmol) was added DMF (9 ml).The mixture was purged with Ar for 10 min and Pd(OAc)₂ (0.275 g, 1.226mmol) was added. The reaction was heated at 120° C. for 15 h. Thereaction was partitioned between water (50 ml) and EtOAc (50 ml) andsolution was filtered through paper and the layers were separated. Theaqueous layer was extracted with EtOAc (2×50 ml). The combined organiclayers were washed with brine (50 ml), dried over MgSO₄, filtered andconcentrated. The residue was purified by normal phase chromatographyusing hexanes and EtOAc as eluents to afford (S)-tert-butyl(1-(3-(1-methyl-4-nitro-1H-pyrazol-5-yl)phenyl)but-3-en-1-yl)carbamate(1.186 g, 3.18 mmol, 51.9% yield) as a yellow oil. MS(ESI) m/z: 371.1(M−H)⁺.

31B. Preparation of tert-butylN-[(1S)-1-[3-(4-amino-1-methyl-1H-pyrazol-5-yl)phenyl]but-3-en-1-yl]carbamate

To tert-butylN-[(1S)-1-[3-(1-methyl-4-nitro-1H-pyrazol-5-yl)phenyl]but-3-en-1-yl]carbamate(0.097 g, 0.260 mmol) in acetone (5 ml)/water (1 ml), cooled to 0° C.,was added NH₄Cl (0.070 g, 1.302 mmol) and Zn (0.170 g, 2.60 mmol). Theice bath was removed. After 3 h, the reaction was filtered and thefiltrate was partitioned between water (10 ml) and EtOAc (30 ml). Theaqueous layer was extracted with EtOAc (2×20 ml). The combined organiclayers were washed with brine (10 ml), dried over MgSO₄, filtered andconcentrated. The residue was purified by normal phase chromatographyusing DCM and 0-10% MeOH as eluents to afford tert-butylN-[(1S)-1-[3-(4-amino-1-methyl-1H-pyrazol-5-yl)phenyl]but-3-en-1-yl]carbamate(76.6 mg, 86%). MS(ESI) m/z: 343.2 (M+H)⁺.

31C. Preparation of tert-butylN-[(1S)-1-(3-{1-methyl-4-[(2R)-2-methylbut-3-enamido]-1H-pyrazol-5-yl}phenyl)but-3-en-1-yl]carbamate

To tert-butylN-[(1S)-1-[3-(4-amino-1-methyl-1H-pyrazol-5-yl)phenyl]but-3-en-1-yl]carbamate(0.076 g, 0.222 mmol) in EtOAc (0.58 ml) was added(R)-2-methylbut-3-enoic acid (0.027 g, 0.266 mmol), prepared asdescribed in Intermediate 2, in 0.3 mL EtOAc. The mixture was cooled to0° C. and Hunig's Base (0.116 ml, 0.666 mmol) followed by a solution of50% T3P® in EtOAc (0.264 ml, 0.444 mmol) were added. After 3 h, thereaction was partitioned with sat NaHCO₃ (5 ml) and EtOAc (5 ml). Theaqueous layer was extracted with EtOAc (2×10 ml). The combined organiclayers were washed with brine (5 ml), dried over MgSO₄, filtered andconcentrated. The residue was purified by normal phase chromatographyusing hexanes and EtOAc as eluents to afford tert-butylN-[(1S)-1-(3-{1-methyl-4-[(2R)-2-methylbut-3-enamido]-1H-pyrazol-5-yl}phenyl)but-3-en-1-yl]carbamate(69 mg, 73%) as a yellow oil. MS(ESI) m/z: 425.2 (M+H)⁺. ¹H NMR (400MHz, CDCl₃) δ 8.04 (s, 1H), 7.52-7.45 (m, 1H), 7.37 (d, J=7.9 Hz, 1H),7.26-7.18 (m, 2H), 7.05 (br. s., 1H), 5.96-5.85 (m, 1H), 5.69 (ddt,J=17.0, 10.1, 7.0 Hz, 1H), 5.21-5.09 (m, 4H), 4.95 (br. s., 1H), 4.77(br. s., 1H), 3.76 (s, 3H), 3.07 (quin, J=7.2 Hz, 1H), 2.61-2.48 (m,2H), 1.45-1.38 (m, 9H), 1.30 (d, J=7.0 Hz, 3H).

31D. Preparation of tert-butylN-[(9R,10E,13S)-3,9-dimethyl-8-oxo-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate

A solution of tert-butylN-[(1S)-1-(3-{1-methyl-4-[(2R)-2-methylbut-3-enamido]-1H-pyrazol-5-yl}phenyl)but-3-en-1-yl]carbamate(0.069 g, 0.163 mmol) in degassed DCE (10 ml) was heated to 120° C. for30 min in a microwave in the presence of Second Generation GrubbsCatalyst (0.055 g, 0.065 mmol). The reaction mixture was directlypurified by normal phase chromatography twice using hexanes and EtOAc aseluents to afford desired tert-butylN-[(9R,10E,13S)-3,9-dimethyl-8-oxo-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate(33 mg, 51.2%) as a dark solid. MS(ESI) m/z: 397.1 (M+H)⁺. ¹H NMR (400MHz, CDCl₃) δ 7.61-7.52 (m, 1H), 7.46-7.40 (m, 1H), 7.33-7.25 (m, 1H),7.20 (d, J=7.5 Hz, 1H), 6.93 (br. s., 1H), 6.83 (s, 1H), 5.63 (ddd,J=15.1, 9.4, 5.6 Hz, 1H), 5.18 (br. s., 1H), 4.89 (dd, J=15.2, 8.8 Hz,1H), 4.69 (br. s., 1H), 3.93-3.86 (m, 3H), 3.09-2.99 (m, 1H), 2.69-2.58(m, 1H), 2.17-2.08 (m, 1H), 1.53-1.32 (m, 9H), 1.18 (d, J=6.8 Hz, 3H).

31E. Preparation of tert-butylN-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate

A solution of tert-butylN-[(9R,10E,13S)-3,9-dimethyl-8-oxo-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate(0.089 g, 0.224 mmol) in EtOH (5 ml) was hydrogenated under a H₂atmosphere at 55 psi for 3 h. The reaction mixture was filtered throughsmall plug of CELITE® and rinsed with EtOH/MeOH/DCM to give tert-butylN-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate(89 mg, 99%) as a white solid. MS(ESI) m/z: 399.4 (M+H)⁺. ¹H NMR (400MHz CDCl₃) δ 7.53-7.43 (m, 2H), 7.43-7.36 (m, 1H), 7.29 (s, 1H), 6.44(s, 1H), 4.90 (br. s., 1H), 4.68 (br. s., 1H), 3.98 (s, 3H), 2.44 (br.s., 1H), 1.93 (d, J=7.7 Hz, 1H), 1.85-1.63 (m, 2H), 1.42 (br. s., 9H),1.28-1.19 (m, 2H), 1.07 (d, J=6.8 Hz, 3H), 0.96 (br. s., 1H).

31F. Preparation of(9R,13S)-13-amino-3,9-dimethyl-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one hydrochloride

tert-ButylN-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate(88 mg, 0.221 mmol) was deprotected with 4 N HCl in dioxane (3 ml) for 5h. The reaction was concentrated to afford (70 mg, 95%) of(9R,13S)-13-amino-3,9-dimethyl-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onehydrochloride as a dark solid. MS(ESI) m/z: 299.08 (M+H)⁺. ¹H NMR (500MHz, CD₃OD) δ 7.81 (s, 1H), 7.77-7.70 (m, 1H), 7.70-7.58 (m, 3H), 4.46(dd, J=12.0, 4.5 Hz, 1H), 4.19-4.07 (m, 3H), 3.45-3.26 (m, 1H),2.75-2.59 (m, 1H), 2.21-2.09 (m, 1H), 1.99-1.86 (m, 2H), 1.58 (td,J=14.3, 8.3 Hz, 1H), 1.29-1.17 (m, 1H), 1.03 (d, J=6.9 Hz, 3H),0.94-0.82 (m, 1H).

Intermediate 32 Preparation of(9R,13S)-13-amino-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

32A. Preparation of 1-methyl-4-nitro-1H-pyrazole

To a solution of 4-nitro-1H-pyrazole (2.5 g, 22.11 mmol) in THF (50 mL)was added NaH (0.973 g, 24.32 mmol) and the mixture was stirred at rtfor 5 min. To this suspension was then added CH₃I (1.382 mL, 22.11 mmol)and stirred at rt overnight. The reaction mixture was then diluted withEtOAc (2×25 mL) and washed with brine (25 mL). The organic layer wasconcentrated, followed by purification using normal phase chromatographyto yield 1-methyl-4-nitro-1H-pyrazole as white solid (1.9 g, 80% yield).¹H NMR (400 MHz, CDCl₃) δ ppm 8.12 (s, 1H), 8.06 (s, 1H), 3.97 (s, 3H).

32B. Preparation of (S)-tert-butyl(1-(4-(1-methyl-4-nitro-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate

To a N₂ flushed pressure vial was added (S)-tert-butyl(1-(4-chloropyridin-2-yl)but-3-en-1-yl)carbamate, prepared as describedin Intermediate 23, (3.0 g, 10.61 mmol), 1-methyl-4-nitro-1H-pyrazole(1.348 g, 10.61 mmol), di(adamant-1-yl)(butyl) phosphine (1.141 g, 3.18mmol), PvOH (0.369 ml, 3.18 mmol), K₂CO₃ (4.40 g, 31.8 mmol) and DMF (21mL). The reaction mixture was purged with N₂ for 5 min and Pd(OAc)₂(0.476 g, 2.122 mmol) was added. The reaction mixture was purged withN₂. The vial was sealed and heated at 120° C. for 4 h. The reactionmixture was cooled to rt and partitioned between 10% aqueous LiCl (15mL) and EtOAc (30 mL). The aqueous layer was extracted with EtOAc (2×20mL) and the combined organic layers were washed with brine (15 mL),dried over MgSO₄, filtered and concentrated. The crude product was thenpurified using normal phase chromatography to yield (S)-tert-butyl(1-(4-(1-methyl-4-nitro-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate(1.2 g, 29% yield) as a brown oil. MS(ESI) m/z: 374.4 (M+H)⁺.

32C. Preparation of (S)-tert-butyl(1-(4-(4-amino-1-methyl-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate

A solution of (S)-tert-butyl(1-(4-(1-methyl-4-nitro-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate(1.2 g, 3.21 mmol) in MeOH (10 mL) and AcOH (1 mL) was heated to 40° C.To the above clear solution was then slowly added Zn (0.420 g, 6.43mmol) in 3 portions (50:25:25%) and stirred at 40° C. for 5 min. Thereaction mixture was monitored by LCMS and once complete, the solutionwas cooled to rt, and K₂CO₃ and 1 mL water were added. The reactionmixture was stirred for 5 min, then filtered through a pad of CELITE®and concentrated to yield the crude product. The crude product waspartitioned between EtOAc (30 mL) and sat NaHCO₃ (15 mL). The organiclayers were separated and dried over MgSO₄. The crude product waspurified using normal phase chromatography to yield (S)-tert-butyl(1-(4-(4-amino-1-methyl-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate(0.88 g, 76% yield) as pale brown oil. MS(ESI) m/z: 344.4 (M+H)⁺.

32D. Preparation of tert-butyl((S)-1-(4-(1-methyl-4-((R)-2-methylbut-3-enamido)-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate

To a N₂ flushed, 3-necked, 250 mL RBF was added a solution of(S)-tert-butyl(1-(4-(4-amino-1-methyl-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate(620 mg, 1.805 mmol) and EtOAc (15 mL). The solution was cooled to −10°C. and (R)-2-methylbut-3-enoic acid, as prepared in Intermediate 2, (271mg, 2.71 mmol), pyridine (0.437 mL, 5.42 mmol) and T3P® (2.149 mL, 3.61mmol) were added. The cooling bath was removed and the solution wasallowed to warm to rt and then stir over a period of 20 h. Water (15 mL)and EtOAc (15 mL) were added and the mixture was stirred for 30 min. Theorganic phase was separated and the aqueous layer was extracted withEtOAc (15 mL). The combined organic extracts were washed with brine (15mL), dried over Na₂SO₄, filtered and concentrated. Purification bynormal phase chromatography eluting with a gradient of hexanes/EtOAcgave tert-butyl((S)-1-(4-(1-methyl-4-((R)-2-methylbut-3-enamido)-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate(0.26 g, 34% yield). MS(ESI) m/z: 426.5 [M+H]⁺.

32E. Preparation of tert-butylN-[(9R,10E,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate

To a N₂ flushed, 250 mL, 3-necked RBF was added a solution of tert-butyl((S)-1-(4-(1-methyl-4-((R)-2-methylbut-3-enamido)-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate(266 mg, 0.625 mmol) in DCE (18 mL). The solution was sparged with Arfor 15 min. Second Generation Grubbs Catalyst (213 mg, 0.250 mmol) wasadded in one portion. The reaction mixture was heated to 120° C. inmicrowave for 30 min. After cooling to rt, the solvent was removed andthe residue was purified by normal phase chromatography eluting with agradient of DCM/MeOH to yield tert-butylN-[(9R,10E,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate(60 mg, 23% yield) as a tan solid. MS(ESI) m/z: 398.4 [M+H]⁺.

32F. Preparation of tert-butylN-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate

Pd/C (0.016 g, 0.015 mmol) was added to a 100 mL Parr hydrogenationflask containing a solution of tert-butylN-[(9R,10E,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate(60 mg, 0.151 mmol) in EtOH (6 mL). The flask was purged with N₂ andpressurized to 55 psi of H₂ and allowed to stir for 5 h. The reactionwas filtered through a pad of CELITE® and concentrated to yieldtert-butylN-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate(48 mg, 76% yield) as a tan solid. MS(ESI) m/z: 400.5 [M+H]⁺.

32G. Preparation of(9R,13S)-13-amino-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

To a solution of tert-butylN-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate(48 mg, 0.120 mmol) in DCM (2.5 mL) was added TFA (0.6 mL, 7.79 mmol)and the reaction was stirred at rt for 1.5 h. The reaction mixture wasthen concentrated to give(9R,13S)-13-amino-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onebis trifluoroacetate (63 mg, 94% yield) as a brown solid which was thendissolved in MeOH (1 mL) to give a clear, brown solution. The solutionwas added to a pre-rinsed AGILENT® StratoSpheres SPE PL-HCO₃ MP Resincartridge. Gravity filtration, eluting with MeOH, gave a clear, slightlyyellow filtrate. Concentration provided(9R,13S)-13-amino-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(25 mg, 93%) as a pale yellow solid. MS(ESI) m/z: 300.4 [M+H]⁺.

Intermediate 33 Preparation of(9R,13S)-13-amino-3-(²H₃)methyl-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

33A. Preparation of 1-(²H₃)methyl-4-nitro-1H-pyrazole

DIAD (5.59 mL, 28.7 mmol) was added to a solution of 4-nitro-1H-pyrazole(2.5 g, 22.11 mmol), CD₃OD (0.898 mL, 22.11 mmol), and Ph₃P (resinbound) (8.84 g, 26.5 mmol) in THF (40 ml) and stirred overnight. Thereaction was quenched with water, extracted with EtOAc, washed withbrine, dried over Na₂SO₄, filtered, and concentrated. The crude productwas purified by normal phase chromatography eluting with a gradient ofDCM/MeOH to afford 1-(²H₃)methyl-4-nitro-1H-pyrazole (1.92 g, 14.76mmol, 66.7% yield) as a white solid. MS(ESI) m/z: 131.0 (M+H)⁺. ¹H NMR(400 MHz, CDCl₃) δ 8.13 (d, J=0.4 Hz, 1H), 8.05 (s, 1H).

33B. Preparation of tert-butylN-[(1S)-1-{4-[1-(²H₃)methyl-4-nitro-1H-pyrazol-5-yl]pyridin-2-yl)}but-3-en-1-yl]carbamate

To a large microwave vial were added (S)-tert-butyl(1-(4-chloropyridin-2-yl)but-3-en-1-yl)carbamate (2.61 g, 9.22 mmol),1-(²H₃)methyl-4-nitro-1H-pyrazole (1.0 g, 7.69 mmol),di(adamantan-1-yl)(butyl)phosphine (0.413 g, 1.15 mmol), K₂CO₃ (3.19 g,23.06 mmol), pivalic acid (0.268 ml, 2.306 mmol) and DMF (15.37 ml). Thereaction was purged with Ar for 10 min, Pd(OAc)₂ (0.173 g, 0.769 mmol)was added, the vial sealed, and stirred at 115° C. overnight. Thereaction was then partitioned between EtOAc and H₂O. The aqueous layerwas extracted with EtOAc (2×). The combined organic layer was washedwith brine, dried over MgSO₄, filtered and concentrated. The residue waspurified by normal phase chromatography eluting with a gradient ofhexanes/EtOAc to give tert-butylN-[(1S)-1-{4-[1-(²H₃)methyl-4-nitro-1H-pyrazol-5-yl]pyridin-2-yl}but-3-en-1-yl]carbamate(1.49 g, 3.96 mmol, 51.5% yield) as a lavender foam. MS(ESI) m/z: 377.0(M+H)⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.77 (d, J=4.8 Hz, 1H), 8.21 (s, 1H),7.26 (s, 1H), 7.23 (dd, J=5.1, 1.5 Hz, 1H), 5.78-5.65 (m, 1H), 5.55 (d,J=6.8 Hz, 1H), 5.14-5.03 (m, 2H), 4.89 (d, J=6.8 Hz, 1H), 2.66 (t, J=6.6Hz, 2H), 1.44 (s, 9H).

33C. Preparation of tert-butylN-[(1S)-1-{4-[4-amino-1-(²H₃)methyl-1H-pyrazol-5-yl]pyridin-2-yl)}but-3-en-1-yl]carbamate

tert-Butyl N-[(1S)-1-{4-[1-(²H₃)methyl-4-nitro-1H-pyrazol-5-yl]pyridin-2-yl}but-3-en-1-yl]carbamate(1.45 g, 3.85 mmol) was dissolved in acetone (15 ml)/water (3 ml),cooled to 0° C. NH₄Cl (1.030 g, 19.26 mmol) and Zn (2.52 g, 38.5 mmol)were added and the ice bath was removed. After 1 h, the reaction wasfiltered and filtrate partitioned with water (30 ml) and EtOAc (50 ml).The aqueous layer was extracted with EtOAc (2×50 ml). The combinedorganic layers were washed with brine (20 ml), dried over MgSO₄,filtered, and concentrated. The residue was purified by normal phaseeluting with a gradient of DCM/MeOH chromatography to afford tert-butylN-[(1S)-1-{4-[4-amino-1-(²H₃)methyl-1H-pyrazol-5-yl]pyridin-2-yl}but-3-en-1-yl]carbamate(0.62 g, 46.5%). MS(ESI) m/z: 347.2 (M+H)⁺. ¹H NMR (400 MHz, CDCl₃) δ8.67 (dd, J=5.1, 0.7 Hz, 1H), 7.26-7.23 (m, 2H), 7.21 (dd, J=5.1, 1.5Hz, 1H), 5.79-5.66 (m, 1H), 5.58 (d, J=7.3 Hz, 1H), 5.11-5.05 (m, 2H),4.86 (q, J=6.6 Hz, 1H), 2.64 (t, J=6.7 Hz, 2H), 1.44 (s, 9H).

33D. Preparation of tert-butylN-[(1S)-1-{4-[1-(²H₃)methyl-4-[(2R)-2-methylbut-3-enamido]-1H-pyrazol-5-yl]pyridin-2-yl)}but-3-en-1-yl]carbamate

(R)-2-Methylbut-3-enoic acid (233 mg, 2.327 mmol), tert-butylN-[(1S)-1-{4-[4-amino-1-(²H₃)methyl-1H-pyrazol-5-yl]pyridin-2-yl}but-3-en-1-yl]carbamate(620 mg, 1.79 mmol), pyridine (0.433 ml, 5.37 mmol) in EtOAc (17.900 ml)was cooled to −10° C. under Ar. T3P® (50% wt in EtOAc) (2.13 ml, 3.58mmol) was added dropwise and then the reaction mixture was graduallywarmed up to rt. After 3.5 h, the reaction mixture was diluted withEtOAc, washed with 1.5 M K₂HPO₄ followed by brine, dried over Na₂SO₄,filtered, and concentrated. The crude product was then purified bynormal phase chromatography eluting with a gradient of hexanes/EtOAc togive tert-butylN-[(1S)-1-{4-[1-(²H₃)methyl-4-[(2R)-2-methylbut-3-enamido]-1H-pyrazol-5-yl]pyridin-2-yl}but-3-en-1-yl]carbamate(529 mg, 1.234 mmol, 69.0% yield) as a yellow foam. MS(ESI) m/z: 429.2(M+H)⁺.

33E. Preparation of tert-butylN-[(9R,10E,13S)-3-(²H₃)methyl-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate

Five large microwave vials were charged in equal amounts with thefollowing: tert-butylN-[(1S)-1-{4-[1-(²H₃)methyl-4-[(2R)-2-methylbut-3-enamido]-1H-pyrazol-5-yl]pyridin-2-yl}but-3-en-1-yl]carbamate(0.51 g, 1.190 mmol) in degassed DCE (90 ml) was irradiated at 120° C.for 30 min in the presence of Second Generation Grubbs Catalyst (0.404g, 0.476 mmol). The reactions were combined, concentrated, and theresidue purified by normal phase column chromatography eluting with agradient of hexanes/EtOAc to give tert-butylN-[(9R,10E,13S)-3-(²H₃)methyl-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate(0.124 g, 26.0%) as a brown solid. MS(ESI) m/z: 401.2 (M+H)⁺. ¹H NMR(400 MHz, CDCl₃) δ 8.66 (d, J=5.1 Hz, 1H), 7.52 (s, 1H), 7.19 (d, J=4.8Hz, 1H), 6.80 (s, 1H), 6.37 (d, J=7.5 Hz, 1H), 5.68 (t, J=11.2 Hz, 1H),4.82-4.63 (m, 2H), 3.12-2.93 (m, 2H), 1.93 (q, J=11.1 Hz, 1H), 1.48 (s,9H), 1.15 (d, J=5.9 Hz, 3H).

33F. Preparation of tert-butylN-[(9R,13S)-3-(²H₃)methyl-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate

PtO₂ (6.80 mg, 0.030 mmol) was added to a stirring solution oftert-butylN-[(9R,10E,13S)-3-(²H₃)methyl-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate(0.120 g, 0.300 mmol) in EtOH (10 ml). The suspension was subjected to aH₂ atmosphere (55 psi) for 1 h. The catalyst was filtered off through aplug of CELITE® and the filtrate concentrated to give tert-butylN-[(9R,13S)-3-(²H₃)methyl-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate(0.104 g, 86%). MS(ESI) m/z: 403.2 (M+H)⁺.

33G. Preparation of(9R,13S)-13-amino-3-(²H₃)methyl-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

4 M HCl in dioxane (1.62 ml) was added to a stirring solution oftert-butylN-[(9R,13S)-3-(²H₃)methyl-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate(0.100 g, 0.248 mmol) in MeOH (3 ml) and stirred overnight. The reactionmixture was concentrated to dryness and placed under high vacuum. Thehydrochloride salt was free based by dissolution in MeOH, passed througha resin bound NaHCO₃ cartridge (StratoSpheres SPE; 500 mg, 0.90 mmolloading) and filtrate concentrated to give(9R,13S)-13-amino-3-(²H₃)methyl-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one.MS(ESI) m/z: 303.4 (M+H)⁺.

Intermediate 34 Preparation of(9R,13S)-13-amino-3-(²H₃)methyl-9-methyl-3,4,7,17-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

(9R,13S)-13-Amino-3-(²H₃)methyl-9-methyl-3,4,7,17-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onewas prepared in a similar manner as(9R,13S)-13-amino-3-c(²H₃)methyl-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one,as described in Intermediate 33, replacing (S)-tert-butyl(1-(4-chloropyridin-2-yl)but-3-en-1-yl)carbamate, described inIntermediate 23, with (S)-tert-butyl(1-(2-bromopyridin-4-yl)but-3-en-1-yl)carbamate, described inIntermediate 27. MS(ESI) m/z: 303.3 (M+H)⁺. ¹H NMR (400 MHz, CD₃OD) δ8.70 (d, J=5.3 Hz, 1H), 7.58 (s, 1H), 7.50-7.42 (m, 2H), 4.14-4.05 (m,1H), 2.72 (td, J=6.7, 3.5 Hz, 1H), 2.06-1.94 (m, 2H), 1.65-1.50 (m, 2H),1.41-1.26 (m, 1H), 1.02 (d, J=6.8 Hz, 3H), 0.70-0.53 (m, 1H).

Intermediate 35 Preparation of(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

35A. Preparation of tert-butylN-[(1S)-1-{3-[1-(difluoromethyl)-4-nitro-1H-pyrazol-5-yl]phenyl}but-3-en-1-yl]carbamate

To a solution of (S)-tert-butyl(1-(3-bromophenyl)but-3-en-1-yl)carbamate (4.0 g, 12.29 mmol), preparedas described in Intermediate 24, in DMF (40.9 ml), was added1-(difluoromethyl)-4-nitro-1H-pyrazole (2.20 g, 13.49 mmol),di(adamantan-1-yl)(butyl) phosphine (0.659 g, 1.839 mmol), K₂CO₃ (5.08g, 36.8 mmol) and pivalic acid (0.427 ml, 3.68 mmol). The resultingsolution was purged with Ar for 10 min. Pd(OAc)₂ (0.275 g, 1.226 mmol)was added and the reaction mixture was stirred at 115° C. for 4 h. Thereaction was cooled to rt, quenched with water (50 mL) and extractedwith EtOAc (3×50 mL). The combined organic layers were washed with brine(50 mL), dried (MgSO₄), filtered, and concentrated. The residue waspurified by normal phase column chromatography eluting with a gradientof heptane/EtOAc to give tert-butylN-[(1S)-1-{3-[1-(difluoromethyl)-4-nitro-1H-pyrazol-5-yl]phenyl}but-3-en-1-yl]carbamate(4.0 g, 80.0%). MS(ESI) m/z: 407 (M−H)⁻.

35B. Preparation of tert-butylN-[(1S)-1-{3-[4-amino-1-(difluoromethyl)-1H-pyrazol-5-yl]phenyl}but-3-en-1-yl]carbamate

tert-ButylN-[(1S)-1-{3-[1-(difluoromethyl)-4-nitro-1H-pyrazol-5-yl]phenyl}but-3-en-1-yl]carbamate(4.0 g, 9.79 mmol) was dissolved in acetone (100 ml)/H₂O (24 ml) andthen cooled to 0° C. To the solution was added NH₄Cl (2.62 g, 49.0 mmol)and Zn (6.40 g, 98 mmol) and the ice bath was removed. After 2 h, thereaction mixture was filtered and filtrate partitioned between water (30ml) and EtOAc (50 ml). The aqueous layer was extracted with EtOAc (2×50ml). The combined organic phase was washed with brine (20 ml), dried(MgSO₄), filtered, and concentrated. The residue was purified by normalphase chromatography eluting with a gradient of DCM/MeOH to give oftert-butylN-[(1S)-1-{3-[4-amino-1-(difluoromethyl)-H-pyrazol-5-yl]phenyl}but-3-en-1-yl]carbamate(3.33 g, 8.80 mmol, 90%) as a yellow oil. MS(ESI) m/z: 379.2 (M+H)⁺.

35C. Preparation of tert-butylN-[(1S)-1-{3-[1-(difluoromethyl)-4-[(2R)-2-methylbut-3-enamido]-1H-pyrazol-5-yl]phenyl}but-3-en-1-yl]carbamate

To a solution of tert-butylN-[(1S)-1-{3-[4-amino-1-(difluoromethyl)-1H-pyrazol-5-yl]phenyl)}but-3-en-1-yl]carbamate(3.3 g, 8.72 mmol) in EtOAc (20 ml) at 0° C. was added(R)-2-methylbut-3-enoic acid (1.048 g, 10.46 mmol), prepared asdescribed in Intermediate 2, in EtOAc (10 ml), pyridine (2.116 ml, 26.2mmol), and T3P®/50% EtOAc (10.38 ml, 17.44 mmol). After 4 h, thereaction was diluted with EtOAc, and washed with a solution of K₂HPO₄,followed by brine. The organic layer was dried over Na₂SO₄, filtered,and concentrated. The residue was purified normal phase columnchromatography eluting with a gradient of hexanes/EtOAc to givetert-butylN-[(1S)-1-{3-[1-(difluoromethyl)-4-[(2R)-2-methylbut-3-enamido]-1H-pyrazol-5-yl]phenyl}but-3-en-1-yl]carbamate(3.10 g, 6.73 mmol, 77% yield) as a yellow foam. MS(ESI) m/z: 461.2(M+H)⁺.

35D. Preparation of tert-butylN-[(9R,10E,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate

To a solution of tert-butylN-[(1S)-1-{3-[1-(difluoromethyl)-4-[(2R)-2-methylbut-3-enamido]-1H-pyrazol-5-yl]phenyl}but-3-en-1-yl]carbamate(3.0 g, 6.51 mmol) in degassed DCM (800 mL), was added Second GenerationGrubbs Catalyst (2.212 g, 2.61 mmol) and the reaction was heated to 40°C. After stirring overnight, the mixture was concentrated and theresidue was purified by normal phase column chromatography eluting witha gradient of hexanes/EtOAc to give tert-butylN-[(9R,10E,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate(1.8 g, 63.9%). MS(ESI) m/z: 433.2 (M+H)⁺.

35E. Preparation of tert-butylN-[(9R,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate

To a solution of tert-butylN-[(9R,10E,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate(1.3 g, 3.01 mmol) in EtOH (50 ml) was added PtO₂ (0.102 g, 0.451 mmol)and the reaction was hydrogenated at 55 psi for 4 h. The reactionmixture was filtered through a plug of CELITE® and the filtrateconcentrated to give tert-butylN-[(9R,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate(0.973 g, 74.5%). MS(ESI) m/z: 435.2 (M+H)⁺.

35F. Preparation of(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

To a solution of tert-butylN-[(9R,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate(0.973 g, 2.239 mmol) in DCM (50 ml) was added TFA (5.18 ml, 67.2 mmol).After 3 h, the reaction mixture was concentrated to dryness. The residuewas partitioned between sat NaHCO₃ and EtOAc. The aqueous phase wasextracted with EtOAc (3×), washed with brine, dried over Na₂SO₄,filtered, and concentrated to give(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(0.619 g, 83%). MS(ESI) m/z: 335 (M+H)⁺.

Intermediate 36 Preparation of(9R,13S)-13-amino-3-(²H₃)methyl-9-methyl-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

36A. Preparation of tert-butylN-[(1S)-1-{3-[1-(²H₃)methyl-4-nitro-1H-pyrazol-5-yl]phenyl}but-3-en-1-yl]carbamate

To a solution of tert-butylN-[(1S)-1-(3-bromophenyl)but-3-en-1-yl]carbamate (3.8 g, 11.65 mmol) inDMF (35 ml), was added 1-(²H₃)methyl-4-nitro-1H-pyrazole (1.667 g, 12.81mmol), di(adamantan-1-yl)(butyl)phosphine (0.626 g, 1.747 mmol), K₂CO₃(4.83 g, 34.9 mmol) and pivalic acid (0.406 ml, 3.49 mmol). The reactionwas purged with Ar and Pd(OAc)₂ (0.262 g, 1.165 mmol) was added. Thereaction was heated to 115° C. After 4 h, the reaction was diluted with1:1 EtOAc/water (50 ml) and filtered through paper to remove Pd solids.The filtrate was extracted with EtOAc (2×50 ml). The combined organiclayer was washed with water (20 ml), brine (20 ml), dried (MgSO₄),filtered and concentrated. The residue was purified by normal phasechromatography twice using hexanes and EtOAc as eluents to affordtert-butyl-N-[(1S)-1-{3-[1-(²H₃)methyl-4-nitro-1H-pyrazol-5-yl]phenyl}but-3-en-1-yl]carbamate(1.89 g, 43.2%) as a brown oil. MS(ESI) m/z: 374.4 (M−H)⁺.

36B. Preparation of tert-butyl N-[(1S)-1-{3-[4-amino-1-(²H₃)methyl-1H-pyrazol-5-yl]phenyl}but-3-en-1-yl]carbamate

To a cooled (0° C.) solution of tert-butylN-[(1S)-1-{3-[1-(²H₃)methyl-4-nitro-1H-pyrazol-5-yl]phenyl}but-3-en-1-yl]carbamate(1.89 g, 5.03 mmol), dissolved in acetone (40 ml)/water (12 ml) wasadded NH₄Cl (1.346 g, 25.2 mmol) and Zn (3.29 g, 50.3 mmol). The icebath was removed and the solution was allowed to warm to rt. After 3 h,the reaction was filtered through paper and the filtrate was partitionedbetween water (20 ml) and EtOAc (75 ml). The aqueous layer was extractedwith EtOAc (2×50 ml). The combined organic layers were washed with brine(25 ml), dried (MgSO₄), filtered and concentrated. The residue waspurified by normal phase chromatography using hexanes and EtOAc and thenDCM/0-10% MeOH as eluents to afford tert-butylN-[(1S)-1-{3-[4-amino-1-(²H₃)methyl-1H-pyrazol-5-yl]phenyl}but-3-en-1-yl]carbamate(0.84 g, 48.3%) as a light brown foam. MS(ESI) m/z: 346.5 (M+H)⁺.

36C. Preparation of tert-butylN-[(1S)-1-{3-[1-(²H₃)methyl-4-[(2R)-2-methylbut-3-enamido]-1H-pyrazol-5-yl]phenyl}but-3-en-1-yl]carbamate

To tert-butylN-[(1S)-1-{3-[4-amino-1-(²H₃)methyl-1H-pyrazol-5-yl]phenyl}but-3-en-1-yl]carbamate(0.7 g, 2.026 mmol) in EtOAc (6 ml) was added (R)-2-methylbut-3-enoicacid (0.26 g, 2.63 mmol), prepared as described in Intermediate 2, in 1mL EtOAc. The mixture was cooled to 0° C. and pyridine (0.49 ml, 6.08mmol) followed by a solution of 50% T3P® in EtOAc (2.41 ml, 4.05 mmol)were added. After 1 h, the reaction was partitioned with sat NaHCO₃ (30ml) and EtOAc (50 ml). The aqueous layer was extracted with EtOAc (2×50ml). The combined organic layers were washed with brine (25 ml), dried(MgSO₄), filtered and concentrated. The residue was purified by normalphase chromatography using hexanes and EtOAc as eluents to affordtert-butylN-[(1S)-1-{3-[1-(²H₃)methyl-4-[(2R)-2-methylbut-3-enamido]-1H-pyrazol-5-yl]phenyl}but-3-en-1-yl]carbamate(0.69 g, 81%) as a rose oil. MS(ESI) m/z: 428.5 (M+H)⁺. ¹H NMR (400 MHz,CDCl₃) δ 8.07-7.93 (m, 1H), 7.53-7.44 (m, 1H), 7.37 (d, J=7.9 Hz, 1H),7.28-7.09 (m, 3H), 5.89 (ddd, J=17.4, 9.9, 7.9 Hz, 1H), 5.76-5.60 (m,1H), 5.25-5.11 (m, 4H), 5.07 (d, J=7.0 Hz, 1H), 4.77 (br. s., 1H), 3.08(quin, J=7.2 Hz, 1H), 2.62-2.47 (m, 2H), 1.41 (br. s., 9H), 1.30 (s,3H).

36D. Preparation of tert-butylN-[(9R,10E,13S)-3-(²H₃)methyl-9-methyl-8-oxo-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate

To a degassed DCM (200 ml) solution of tert-butylN-[(1S)-1-{3-[1-(²H₃)methyl-4-[(2R)-2-methylbut-3-enamido]-1H-pyrazol-5-yl]phenyl}but-3-en-1-yl]carbamate(0.699 g, 1.635 mmol) was added Second Generation Grubbs Catalyst (0.555g, 0.654 mmol) and the resulting solution was heated to 40° C. for 24 h.The reaction mixture was concentrated and the residue was purified bynormal phase chromatography using DCM and 0-10% MeOH as eluents toafford tert-butylN-[(9R,10E,13S)-3-(²H₃)methyl-9-methyl-8-oxo-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate(0.511 g, 78%) as a dark solid. MS(ESI) m/z: 400.2 (M+H)⁺. ¹H NMR (400MHz, CDCl₃) δ 7.65-7.56 (m, 1H), 7.51-7.44 (m, 1H), 7.30 (d, J=7.9 Hz,1H), 7.23 (d, J=7.7 Hz, 1H), 6.85 (s, 1H), 6.68 (s, 1H), 5.66 (ddd,J=15.2, 9.3, 5.6 Hz, 1H), 5.20-5.06 (m, 1H), 4.94 (dd, J=15.3, 8.5 Hz,1H), 4.78-4.66 (m, 1H), 3.08-2.99 (m, 1H), 2.71-2.58 (m, 1H), 2.23-2.12(m, 1H), 1.43 (br. s., 9H), 1.25-1.19 (m, 3H).

36E. Preparation of tert-butylN-[(9R,13S)-3-(²H₃)methyl-9-methyl-8-oxo-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate

To a EtOH (20 ml) solution of tert-butylN-[(9R,10E,13S)-3-(²H₃)methyl-9-methyl-8-oxo-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate(0.40 g, 1.001 mmol) was added PtO₂ (0.023 g, 0.100 mmol). The reactionvessel was purged with H₂ and the reaction mixture was then hydrogenatedat 55 psi. After 1.5 h under pressure, the reaction mixture was thenallowed to sit overnight under N₂. The reaction was then filteredthrough CELITE® rinsing with DCM and EtOH. The filtrate wasconcentration of the afforded tert-butylN-[(9R,13S)-3-(²H₃)methyl9-methyl-8-oxo-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate(0.38 g, 95%) as a brown solid. MS(ESI) m/z: 402.5 (M+H)⁺.

36F. Preparation of(9R,13S)-13-amino-3-(²H₃)methyl-9-methyl-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

To a dioxane (2 ml) and MeOH (2 ml) solution of tert-butylN-[(9R,13S)-3-(²H₃)methyl-9-methyl-8-oxo-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate(0.38 g, 0.946 mmol) was added 4 N HCl in dioxane (2 ml). After 4 h, thereaction was concentrated to near dryness. The dry residue was dissolvedin MeOH/DCM and filtered through 500 mg basic cartridge and the filtratewas concentrated to afford(9R,13S)-13-amino-3-(²H₃)methyl-9-methyl-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(0.28 g, 98%) as a gray solid. MS(ESI) m/z: 302.5 (M+H)⁺.

Intermediate 37 Preparation of(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,17-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

37A. Preparation of (S)-tert-butyl(1-(2-(1-(difluoromethyl)-4-nitro-1H-pyrazol-5-yl)pyridin-4-yl)but-3-en-1-yl)carbamate

To a large microwave vial was added (S)-tert-butyl(1-(2-bromopyridin-4-yl)but-3-en-1-yl)carbamate (1.5 g, 4.58 mmol),prepared as described for Intermediate 27,1-(difluoromethyl)-4-nitro-1H-pyrazole (0.822 g, 5.04 mmol), prepared asdescribed for Intermediate 30A, DMF (15.3 mL),di(adamantan-1-yl)(butyl)phosphine (0.247 g, 0.688 mmol), K₂CO₃ (1.901g, 13.75 mmol) and pivalic acid (0.160 mL, 1.375 mmol). The mixture waspurged with Ar for 15 min. Pd(OAc)₂ (0.103 g, 0.458 mmol) was added, thevial sealed and stirred at 115° C. After 4 h, the reaction was quenchedwith water (50 mL) and extracted with EtOAc (3×50 mL). The combinedorganic layers were washed with brine (50 mL), dried (MgSO₄), filtered,and concentrated to give a dark brown oil. The crude product waspurified by normal phase chromatography using heptane and EtOAc aseluents to give (S)-tert-butyl(1-(2-(1-(difluoromethyl)-4-nitro-1H-pyrazol-5-yl)pyridin-4-yl)but-3-en-1-yl)carbamate(973 mg, 52%) as a orange solid. MS(ESI) m/z: 410.1 (M+H)⁺. ¹H NMR (500MHz, CDCl₃) δ 8.73 (d, J=5.2 Hz, 1H), 8.38 (s, 1H), 7.74 (br. s., 1H),7.63-7.48 (m, 1H), 7.44-7.37 (m, 1H), 5.69 (ddt, J=17.0, 10.1, 7.0 Hz,1H), 5.24-5.17 (m, 2H), 2.62-2.50 (m, 2H), 1.45 (s, 9H).

37B. Preparation of (S)-tert-butyl(1-(2-(4-amino-1-(difluoromethyl)-1H-pyrazol-5-yl)pyridin-4-yl)but-3-en-1-yl)carbamate

(S)-tert-Butyl(1-(2-(1-(difluoromethyl)-4-nitro-1H-pyrazol-5-yl)pyridin-4-yl)but-3-en-1-yl)carbamate(0.974 g, 2.379 mmol) was dissolved in acetone (15 mL)/water (3 mL),cooled to 0° C., and NH₄Cl (0.636 g, 11.90 mmol) and Zn (1.555 g, 23.79mmol) were added. After stirring overnight at rt, the reaction mixturewas filtered through a plug of CELITE® and the filtrate wasconcentrated. The residue was partitioned with water (30 mL) and EtOAc(50 mL). The aqueous layer was extracted with EtOAc (2×50 mL). Thecombined organic layers were washed with brine (20 mL) and dried(MgSO₄). The product was carried forward as is. MS(ESI) m/z: 380.1(M+H)⁺.

37C. Preparation of tert-butyl((S)-1-(2-(1-(difluoromethyl)-4-((R)-2-methylbut-3-enamido)-1H-pyrazol-5-yl)pyridin-4-yl)but-3-en-1-yl)carbamate

To a stirring solution of (S)-tert-butyl(1-(2-(4-amino-1-(difluoromethyl)-1H-pyrazol-5-yl)pyridin-4-yl)but-3-en-1-yl)carbamate(0.900 g, 2.372 mmol) in EtOAc (7.91 mL) at 0° C.,(R)-2-methylbut-3-enoic acid (0.309 g, 3.08 mmol) in EtOAc (0.50 mL)T3P®/50% EtOAc (2.82 mL, 4.74 mmol) and pyridine (0.576 mL, 7.12 mmol)were added. After 5 h, the reaction mixture concentrated and purified bynormal phase chromatography using hexanes and EtOAc as eluents to affordtert-butyl((S)-1-(2-(1-(difluoromethyl)-4-((R)-2-methylbut-3-enamido)-1H-pyrazol-5-yl)pyridin-4-yl)but-3-en-1-yl)carbamate(680 mg, 62.1%) as an oil. MS(ESI) m/z: 462.2 (M+H)⁺. ¹H NMR (500 MHz,CDCl₃-d) δ 10.74 (br. s., 1H), 8.60 (s, 1H), 8.57 (d, J=5.2 Hz, 1H),7.84 (s, 1H), 7.58-7.42 (m, 1H), 7.23-7.20 (m, 1H), 6.00 (ddd, J=17.3,10.1, 8.1 Hz, 1H), 5.72-5.62 (m, 1H), 5.36-5.31 (m, 2H), 5.21-5.15 (m,2H), 3.22 (quin, J=7.2 Hz, 1H), 2.59-2.47 (m, 2H), 1.48-1.37 (m, 12H).

37D. Preparation of tert-butylN-[(9R,10E,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,17-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate

3 large microwave vials received equal portions of the following:tert-butyl((S)-1-(2-(1-(difluoromethyl)-4-((R)-2-methylbut-3-enamido)-1H-pyrazol-5-yl)pyridin-4-yl)but-3-en-1-yl)carbamate(0.680 g, 1.473 mmol) in degassed DCE (61.4 mL) in the presence ofSecond Generation Grubbs Catalyst (0.500 g, 0.589 mmol) was irradiatedto 120° C. for 30 min in a wave. The reaction mixture was concentratedand purified by normal phase chromatography using hexanes and EtOAc aseluents to give tert-butylN-[(9R,10E,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,17-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate(158 mg, 24.7%) as a brown film. MS(ESI) m/z: 434.2 (M+H)⁺. ¹H NMR (500MHz, CDCl₃-d) δ 8.69 (d, J=5.0 Hz, 1H), 8.05-7.89 (m, 1H), 7.83 (s, 1H),7.10 (s, 1H), 6.77 (br. s., 1H), 5.73 (ddd, J=15.2, 9.7, 5.1 Hz, 1H),5.13-5.05 (m, 2H), 3.19-3.10 (m, 1H), 2.73 (d, J=12.7 Hz, 1H), 2.24-2.15(m, 1H), 1.46 (br. s., 9H), 1.30-1.24 (m, 4H).

37E. Preparation of tert-butylN-[(9R,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,17-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate

PtO₂ (8.28 mg, 0.036 mmol) was added to a solution of tert-butylN-[(9R,10E,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,17-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate(0.158 g, 0.365 mmol) in EtOH (10 mL) and subjected to a H₂ atmosphere(55 psi). After 3 h, the catalyst was filtered through a pad of CELITE®and filtrate concentrated to give tert-butylN-[(9R,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,17-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate.MS(ESI) m/z: 436.1 (M+H)⁺.

37F. Preparation of(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,17-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

tert-ButylN-[(9R,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,17-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate(0.159 g, 0.365 mmol) was dissolved in MeOH (0.50 mL) and treated with 4M HCl in dioxane (1.83 mL, 7.30 mmol). After stirring for 14 h, thereaction mixture was concentrated to dryness. The amine HCl salt wasfree based by dissolving in MeOH and passing through 2 consecutiveNaHCO₃ cartridges. The filtrate was concentrated(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,17-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(0.085 g, 69%). MS(ESI) m/z: 336.1 (M+H)⁺.

Intermediate 38 Preparation of(10R,14S)-14-amino-10-methyl-3,8-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2,4,6,15,17-hexaen-9-one

38A. Preparation of{3-[(1S)-1-{[(tert-butoxy)carbonyl]amino}but-3-en-1-yl]phenyl}boronicacid

To a solution of tert-butylN-[(1S)-1-(3-bromophenyl)but-3-en-1-yl]carbamate, prepared as describedin Intermediate 24, (2.36 g, 7.23 mmol) in dioxane (50 ml), was added5,5,5′,5′-tetramethyl-2,2′-bi(1,3,2-dioxaborinane) (1.798 g, 7.96 mmol),and KOAc (2.130 g, 21.70 mmol). The mixture was purged with Ar andPdCl₂(dppf)-CH₂Cl₂ adduct (0.295 g, 0.362 mmol) was added. The reactionmixture was heated to 90° C. for 18 h, then quenched with water (20 ml)and extracted with EtOAc (3×30 ml). The combined organic layers werewashed with brine (20 ml), dried (Na₂SO₄), filtered and concentrated.The residue was absorbed on CELITE® and charged to a 100 g reverse phasecartridge which was eluted with a 25 min gradient from 10-100% Solvent B(Solvent A: 90% H₂O—10% MeCN—0.05% TFA; Solvent B: 90% MeCN—10%H₂O—0.05% TFA) to give {3-[(1S)-1-{[(tert-butoxy)carbonyl]amino}but-3-en-1-yl]phenyl}boronic acid asa tan solid. MS(ESI) m/z: 292.08 (M+H)⁺.

38B. Preparation of tert-butyl N-[(1S)-1-[3-(3-aminopyridin-2-yl)phenyl]but-3-en-1-yl]carbamate

{3-[(1 S)-1-{[(tert-Butoxy)carbonyl]amino}but-3-en-1-yl]phenyl}boronicacid (0.36 g, 1.236 mmol), 2-bromopyridin-3-amine (0.214 g, 1.236 mmol),and 2 M aq Na₂CO₃ (3.09 ml, 6.18 mmol) were added to dioxane (8 ml) andpurged with a stream of Ar for 10 min. Pd(PPh₃)₄ (0.143 g, 0.124 mmol)was added and the reaction mixture was irradiated in microwave at 120°C. for 30 min. The reaction was quenched with water (20 ml) andextracted with EtOAc (3×30 ml). The combined organic layers were washedwith brine (15 ml), dried (MgSO₄), filtered and concentrated. Theresidue was purified via Isco 40 g column eluting with DCM/0-10% MeOH togive a tan foam (0.352 g, 84%). The reaction mixture was filtered andconcentrated and the residue was purified by normal phase chromatographyusing DCM and 0-10% MeOH as eluents to afford tert-butylN-[(1S)-1-[3-(3-aminopyridin-2-yl)phenyl]but-3-en-1-yl]carbamate (0.352g, 84%) as a tan solid. MS(ESI) m/z: 340.5 (M+H)⁺. ¹H NMR (400 MHz,CDCl₃) δ 8.13 (dd, J=4.1, 1.9 Hz, 1H), 7.62-7.54 (m, 2H), 7.44 (t, J=7.6Hz, 1H), 7.26 (s, 2H), 7.12-7.00 (m, 2H), 5.82-5.57 (m, 1H), 5.23-5.02(m, 1H), 4.91 (br. s., 1H), 4.80 (br. s., 1H), 3.82 (br. s., 2H),2.81-2.41 (m, 2H), 1.51-1.34 (m, 9H).

38C. Preparation of tert-butylN-[(1S)-1-(3-{3-[(2R)-2-methylbut-3-enamido]pyridin-2-yl}phenyl)but-3-en-1-yl]carbamate

To a cooled (0° C.) EtOAc (6 mL) solution of tert-butylN-[(1S)-1-[3-(3-minopyridin-2-yl)phenyl]but-3-en-1-yl]carbamate (0.334g, 1.03 mmol) was added (R)-2-methylbut-3-enoic acid (0.135 g, 1.348mmol), prepared as described in Intermediate 2, in 1 ml EtOAc, pyridine(0.252 ml, 3.11 mmol) and the dropwise addition of a 50% EtOAc solutionof T3P® (1.235 ml, 2.074 mmol). After 1 h, the reaction was partitionedbetween sat NaHCO₃ (30 ml) and EtOAc (50 ml). The aqueous layer wasextracted with EtOAc (2×50 ml). The combined organic layers were washedwith brine (25 ml) dried (MgSO₄), filtered and concentrated. The residuewas purified by normal phase chromatography using hexanes and EtOAc aseluents to afford tert-butylN-[(1S)-1-(3-{3-[(2R)-2-methylbut-3-enamido]pyridin-2-yl}phenyl)but-3-en-1-yl]carbamate(0.334 g, 76%) as a tan solid. MS(ESI) m/z: 428.5 (M+H)⁺. ¹H NMR (400MHz, CDCl₃) δ 8.71 (dd, J=8.3, 1.2 Hz, 1H), 8.41 (dd, J=4.6, 1.5 Hz,1H), 7.60 (br. s., 1H), 7.49-7.42 (m, 2H), 7.42-7.36 (m, 2H), 7.29 (dd,J=8.4, 4.8 Hz, 1H), 5.84-5.62 (m, 2H), 5.16-5.02 (m, 4H), 4.92 (br. s.,1H), 4.80 (br. s., 1H), 3.04 (quin, J=7.3 Hz, 1H), 2.62-2.48 (m, 2H),1.51-1.35 (m, 9H), 1.32-1.25 (m, 3H).

38D. Preparation of tert-butylN-[(10R,11E,14S)-10-methyl-9-oxo-3,8-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,11,15,17-heptaen-14-yl]carbamate trifluoroacetate

To a in degassed DCE (20 ml) solution of tert-butylN-[(1S)-1-(3-{3-[(2R)-2-methylbut-3-enamido]pyridin-2-yl}phenyl)but-3-en-1-yl]carbamate(0.15 g, 0.356 mmol) was added Second Generation Grubbs Catalyst (0.121g, 0.142 mmol) and the resulting solution was heated to 120° C. for 30min in a microwave. The reaction was concentrated, and the residuepurified by normal phase chromatography, then reverse phase preparativeHPLC (PHENOMENEX® Luna Axia C18 5 i 30×100 mm column, 8-min gradient;Solvent A: 30% MeOH—70% H₂O— 0.1% TFA; Solvent B: 90% MeOH—10% H₂O—0.1%TFA) to afford tert-butylN-[(10R,11E,14S)-10-methyl-9-oxo-3,8-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,11,15,17-heptaen-14-yl]carbamatetrifluoroacetate (71 mg, 39%) as a clear residue. MS(ESI) m/z: 394.5(M+H)⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.73 (d, J=4.4 Hz, 1H), 8.44 (d, J=7.9Hz, 1H), 7.99-7.89 (m, 1H), 7.69-7.59 (m, 1H), 7.59-7.48 (m, 2H),7.17-7.08 (m, 1H), 5.84-5.67 (m, 1H), 4.67-4.53 (m, 1H), 4.53-4.38 (m,1H), 3.28-3.17 (m, 1H), 2.77-2.66 (m, 1H), 2.04 (q, J=11.4 Hz, 1H), 1.46(br. s., 9H), 1.18-1.09 (m, 3H).

38E. Preparation of tert-butylN-[(10R,14S)-10-methyl-9-oxo-3,8-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-14-yl]carbamate

To a EtOH (5 ml) solution of tert-butylN-[(10R,11E,14S)-10-methyl-9-oxo-3,8-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,11,15,17-heptaen-14-yl]carbamate (0.37 g, 0.940 mmol)(free base was prepared as in Example 38D) was added PtO₂ (21 mg) andthe reaction mixture was purged with H₂ and was hydrogenated at 20-30psi for 4 h. The reaction was filtered through CELITE® and the filtratewas concentrated to afford tert-butylN-[(10R,14S)-10-methyl-9-oxo-3,8-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-14-yl]carbamate(0.37 g, 99%) as a dark solid. MS(ESI) m/z: 396.3 (M+H)⁺.

38F. Preparation of(10R,14S)-14-amino-10-methyl-3,8-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-9-one

tert-ButylN-[(10R,14S)-10-methyl-9-oxo-3,8-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-14-yl]carbamate (0.18 g, 0.455 mmol) was dissolvedin 4 N HCl in dioxane (2 ml) and MeOH (2 ml). After 2 h, the reactionwas concentrated, the residue was dissolved in DCM/MeOH and free-basedby passing through a 500 mg basic cartridge (2×). Concentration of thefiltrate afforded(10R,14S)-14-amino-10-methyl-3,8-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-9-one (0.11 g, 49%) as a dark brown film.MS(ESI) m/z: 296.3 (M+H)⁺.

Intermediate 39 Preparation of(10R,14S)-14-amino-10-methyl-3,8,16-triazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-9-one

39A. Preparation of (S)-tert-butyl(1-(3-amino-[2,4′-bipyridin]-2′-yl)but-3-en-1-yl)carbamate

To a solution of(S)-(2-(1-((tert-butoxycarbonyl)amino)but-3-en-1-yl)pyridin-4-yl)boronicacid trifluoroacetate (0.60 g, 1.477 mmol) in dioxane (12 ml) was added2-bromopyridin-3-amine (0.256 g, 1.477 mmol) and 2 M aq Na₂CO₃ (3.69 ml,7.39 mmol). The reaction mixture was purged with a stream of Ar for 10min. Pd(PPh₃)₄ (0.171 g, 0.148 mmol) was added and the mixtureirradiated at 120° C. for 30 min. The reaction was partitioned betweenwater and EtOAc. The organic layer was washed with brine, dried overNa₂SO₄, filtered and concentrated. The crude material was purified bynormal phase column chromatography eluting with a gradient of DCM/MeOHto give (S)-tert-butyl(1-(3-amino-[2,4′-bipyridin]-2′-yl)but-3-en-1-yl)carbamate (0.500 g, 99%yield) as a brown oil. MS(ESI) m/z: 341.1 (M+H)⁺.

39B. Preparation of tert-butyl((S)-1-(3-((R)-2-methylbut-3-enamido)-[2,4′-bipyridin]-2′-yl)but-3-en-1-yl)carbamate

A solution of (R)-2-methylbut-3-enoic acid (0.191 g, 1.909 mmol),prepared as described in Intermediate 2, (S)-tert-butyl(1-(3-amino-[2,4′-bipyridin]-2′-yl)but-3-en-1-yl)carbamate (0.500 g,1.469 mmol), and pyridine (0.356 ml, 4.41 mmol) in EtOAc (14.69 ml) wascooled down to 0° C. under Ar followed by addition of T3P® (50% wt inEtOAc) (1.75 ml, 2.94 mmol), then the reaction mixture was graduallywarmed up to rt. After stirring overnight, the mixture was diluted withEtOAc, washed with 1.5 M K₂HPO₄ followed by brine, dried over Na₂SO₄,filtered, and concentrated. The crude product was then purified bynormal phase chromatography eluting with a gradient of hexanes/EtOAc togive tert-butyl((S)-1-(3-((R)-2-methylbut-3-enamido)-[2,4′-bipyridin]-2′-yl)but-3-en-1-yl)carbamate(0.458 g, 73.8% yield) as a yellow foam. MS(ESI) m/z: 423.2 (M+H)⁺.

39C. Preparation of tert-butylN-[(10R,11E,14S)-10-methyl-9-oxo-3,8,16-triazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,11,15,17-heptaen-14-yl]carbamate,bis-trifluoroacetate

tert-Butyl((S)-1-(3-((R)-2-methylbut-3-enamido)-[2,4′-bipyridin]-2′-yl)but-3-en-1-yl)carbamate(100 mg, 0.237 mmol) in degassed DCE (14.79 ml) in the presence ofSecond Generation Grubbs Catalyst (0.080 g, 0.095 mmol) was irradiatedat 120° C. for 30 min. The reaction mixture was concentrated andpurified by reverse phase chromatography to give the tert-butylN-[(10R,11E,14S)-10-methyl-9-oxo-3,8,16-triazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,11,15,17-heptaen-14-yl]carbamate,bis-trifluoroacetate (39 mg, 26.5% yield) as brown oil. MS(ESI) m/z:395.2 (M+H)⁺.

39D. Preparation of tert-butylN-[(10R,14S)-10-methyl-9-oxo-3,8,16-triazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-14-yl]carbamate

PtO₂ (2.245 mg, 9.89 μmol) was added to a stirring solution oftert-butylN-[(10R,11E,14S)-10-methyl-9-oxo-3,8,16-triazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,11,15,17-heptaen-14-yl]carbamate,bis-trifluoroacetate (0.039 g, 0.099 mmol) in EtOH (10 ml) and subjectedto a H₂ atmosphere (55 psi). After 4 h, the reaction mixture wasfiltered through a pad of CELITE® and the filtrate concentrated to givetert-butylN-[(10R,14S)-10-methyl-9-oxo-3,8,16-triazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-14-yl]carbamate.MS(ESI) m/z: 397.2 (M+H)⁺.

39E. Preparation of(10R,14S)-14-amino-10-methyl-3,8,16-triazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-9-one

TFA (0.15 mL, 1.967 mmol) was added to a solution of tert-butylN-[(10R,14S)-10-methyl-9-oxo-3,8,16-triazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-14-yl]carbamate(0.039 g, 0.098 mmol) in DCM (2.0 ml). After stirring for 4 h, thereaction mixture was concentrated to dryness, and placed under highvacuum for 12 h. The residue was neutral by dissolving in MeOH, passingthrough NaHCO₃ cartridge (StratoSpheres SPE; 500 mg, 0.90 mmol loading),and concentrating the filtrate to give(10R,14S)-14-amino-10-methyl-3,8,16-triazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-9-one.MS(ESI) m/z: 297.5 (M+H)⁺.

Intermediate 40 Preparation of(9R,13S)-13-amino-3-(2-hydroxyethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

40A. Preparation of1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-4-nitro-1H-pyrazole

To a solution of 4-nitro-1H-pyrazole (4.0 g, 35.4 mmol) in DMF (50 mL)was added Cs₂CO₃ (12.68 g, 38.9 mmol) and(2-bromoethoxy)(tert-butyl)dimethylsilane (8.35 mL, 38.9 mmol). Theresulting suspension was heated to 60° C. for 2 h. The reaction mixturewas then diluted with EtOAc (2×25 mL) and washed with 10% LiCl solution(25 mL). The organic layer was concentrated, and the residue purifiedusing normal phase chromatography to yield1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-4-nitro-1H-pyrazole as whitesolid (8.6 g, 85% yield). MS(ESI) m/z: 272.4 (M+H)⁺.

40B. Preparation of (S)-tert-butyl(1-(4-(1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-4-nitro-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate

To a N₂ flushed pressure vial was added (S)-tert-butyl(1-(4-chloropyridin-2-yl)but-3-en-1-yl)carbamate, prepared as describedin Intermediate 23, (3.0 g, 10.61 mmol),1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-4-nitro-1H-pyrazole, preparedas described in Intermediate 40A, (2.88 g, 10.61 mmol),di(adamant-1-yl)(butyl)phosphine (0.571 g, 1.59 mmol), PvOH (0.369 ml,3.18 mmol), K₂C₀₃ (4.40 g, 31.8 mmol), and DMF (20 mL). The vial waspurged with N₂ for 5 min and Pd(OAc)₂ (0.238 g, 1.061 mmol) was added.The reaction mixture was again briefly purged with N₂. The vial wassealed and heated at 120° C. for 4 h. The reaction mixture was cooled tort and partitioned between 10% aqueous LiCl (15 mL) and EtOAc (30 mL).The aqueous layer was extracted with EtOAc (2×20 mL) and the combinedorganic layers were washed with brine (15 mL), dried over MgSO₄,filtered and concentrated. The crude product was purified using normalphase chromatography to yield (S)-tert-butyl(1-(4-(1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-4-nitro-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate(1.4 g, 25% yield) as a brown oil. MS(ESI) m/z: 518.3 (M+H)⁺.

40C. Preparation of (S)-tert-butyl(1-(4-(4-amino-1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate

A solution of (S)-tert-butyl(1-(4-(1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-4-nitro-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate(2.4 g, 4.64 mmol) in MeOH (25 mL) and CH₃COOH (2.5 mL) was heated to40° C. To the resulting clear solution was then slowly added Zn (0.606g, 9.27 mmol, in 3 portions (50:25:25%)) and the reaction was stirred at40° C. for 5 min. Additional Zn was added to the reaction. The reactionmixture was monitored by LCMS and once complete, to the cooled reactionmixture was then added 2.5 g of K₂CO₃ (1 g for 1 mL AcOH) and 2.5 mLwater. The reaction mixture was then stirred for 5 min. The reactionmixture was then filtered over a pad of CELITE® and concentrated toyield the crude product. The crude product was partitioned between EtOAc(40 mL) and sat NaHCO₃ (20 mL). The organic layers were separated, driedover MgSO₄, filtered and concentrated. The crude product was purifiedusing normal phase chromatography to yield (S)-tert-butyl(1-(4-(4-amino-1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate(1.9 g, 80% yield) as pale brown oil. MS(ESI) m/z: 488.6 (M+H)⁺.

40D. Preparation of tert-butyl((S)-1-(4-(1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-4-((R)-2-methylbut-3-enamido)-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate

To a N₂ flushed, 3-necked, 250 mL RBF was added (S)-tert-butyl(1-(4-(4-amino-1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate(1.9 g, 3.90 mmol) and EtOAc (25 mL). The solution was cooled to −10° C.and (R)-2-methylbut-3-enoic acid, as prepared in Intermediate 2, (390mg, 3.90 mmol), pyridine (0.630 mL, 7.79 mmol) and T3P® (3.48 mL, 5.84mmol) were added. The cooling bath was removed and the solution wasallowed to warm to rt and then stirred for 20 h. Water (20 mL) and EtOAc(20 mL) were added and the mixture was stirred for 30 min. The organicphase was separated and the aqueous layer was extracted with EtOAc (20mL). The combined organic extracts were washed with brine (15 mL), driedover Na₂SO₄, filtered and concentrated. Purification by normal phasechromatography eluting with a gradient of hexanes/EtOAc gave((S)-1-(4-(1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-4-((R)-2-methylbut-3-enamido)-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate(0.68 g, 28% yield). MS(ESI) m/z: 570.1 [M+H]⁺.

40E. Preparation of tert-butylN-[(9R,10E,13S)-3-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate

To a N₂ flushed, 250 mL, 3-necked, RBF was added a solution oftert-butyl((S)-1-(4-(1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-4-((R)-2-methylbut-3-enamido)-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate(680 mg, 1.193 mmol) in EtOAc (56 mL). The solution was sparged with Arfor 15 min. Second Generation Grubbs Catalyst (253 mg, 0.298 mmol) wasadded in one portion. The reaction mixture was heated to refluxtemperature for overnight. After cooling to rt, the solvent was removedand the residue was purified by normal phase chromatography eluting witha gradient of DCM/MeOH to yield tert-butylN-[(9R,10E,13S)-3-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate(400 mg, 61% yield) as a tan solid. MS(ESI) m/z: 542.6 [M+H]⁺.

40F. Preparation of tert-butylN-[(9R,13S)-3-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate

Pd/C (0.078 g, 0.074 mmol) was added to a 250 mL Parr hydrogenationflask containing a solution of tert-butylN-[(9R,10E,13S)-3-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate(400 mg, 0.738 mmol) in EtOH (20 mL). The flask was purged with N₂ andpressurized to 55 psi of H₂ and allowed to stir for 4 h. The reactionwas filtered through a pad of CELITE® and concentrated to yieldtert-butylN-[(9R,13S)-3-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate(375 mg, 92% yield) as a tan solid. MS(ESI) m/z: 544.6 [M+H]⁺.

40G.(9R,13S)-13-Amino-3-(2-hydroxyethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

To a solution of tert-butylN-[(9R,13S)-3-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate(375 mg, 0.690 mmol) in MeOH (5 mL) was added 4 N HCl in dioxane (5 mL,20.0 mmol) and the reaction mixture was stirred at rt for 1 h. Thereaction mixture was then concentrated to give(9R,13S)-13-amino-3-(2-hydroxyethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one,bis hydrochloride (220 mg, 96% yield) as a pale yellow solid which wasthen dissolved in MeOH (4 mL) to give a clear, pale yellow solution. Thesolution was added to a pre-rinsed AGILENT® StratoSpheres SPE PL-HCO₃ MPResin cartridge. Gravity filtration, eluting with MeOH, gave a clear,slightly yellow filtrate. Concentration provided(9R,13S)-13-amino-3-(2-hydroxyethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(170 mg, 96%) as a pale yellow solid. MS(ESI) m/z: 330.5 [M+H]⁺.

Intermediate 41 Preparation of(9R,13S)-13-amino-16-fluoro-3,9-dimethyl-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

41A. Preparation of tert-butylN-[(1S)-1-[3-fluoro-5-(1-methyl-4-nitro-1H-pyrazol-5-yl)phenyl]but-3-en-1-yl]carbamate

To a DMF (1 ml) solution of tert-butylN-[(1S)-1-(3-bromo-5-fluorophenyl)but-3-en-1-yl]carbamate (0.19 g, 0.552mmol), prepared as described in Intermediate 25, was added1-methyl-4-nitro-1H-pyrazole (0.070 g, 0.552 mmol),di(adamantan-1-yl)(butyl) phosphine (0.059 g, 0.166 mmol), pivalic acid(0.019 ml, 0.166 mmol), K₂CO₃ (0.229 g, 1.656 mmol) and Pd(OAc)₂ (0.025g, 0.110 mmol). The reaction mixture was purged with Ar, and heated at120° C. After 18 h, the reaction was partitioned between water (15 ml)and EtOAc (30 ml). The aqueous layer was extracted with EtOAc (2×20 ml).The combined organic layers were washed with brine (15 ml), dried(MgSO₄), filtered and concentrated. The residue was purified by normalphase chromatography and was eluted with hexanes and EtOAc to affordtert-butylN-[(1S)-1-[3-fluoro-5-(1-methyl-4-nitro-1H-pyrazol-5-yl)phenyl]but-3-en-1-yl]carbamateas a yellow oil (0.123 g, 57%). ¹H NMR (400 MHz, CDCl₃) δ 8.23-8.17 (m,1H), 7.22-7.16 (m, 1H), 7.10 (s, 1H), 7.01 (dt, J=8.5, 1.9 Hz, 1H),5.76-5.60 (m, 1H), 5.22-5.11 (m, 2H), 4.90 (br. s., 1H), 4.78 (br. s.,1H), 3.78-3.69 (m, 3H), 2.60-2.48 (m, 2H), 1.41 (br. s., 9H).

41B. Preparation of tert-butylN-[(1S)-1-[3-(4-amino-1-methyl-1H-pyrazol-5-yl)-5-fluorophenyl]but-3-en-1-yl]carbamate

tert-ButylN-[(1S)-1-[3-(4-amino-1-methyl-1H-pyrazol-5-yl)-5-fluorophenyl]but-3-en-1-yl]carbamate(0.123 g, 0.315 mmol) was dissolved in acetone (5 ml)/water (1 ml),cooled to 0° C., and NH₄Cl (0.084 g, 1.575 mmol) and Zn (0.206 g, 3.15mmol) were added. The ice bath was removed and the reaction mixture waswarmed to rt. After 3 h, the reaction was filtered and partitionedbetween water (10 ml) and EtOAc (30 ml). The aqueous layer was extractedwith EtOAc (2×20 ml). The combined organic layers were washed with brine(10 ml), dried (MgSO₄), filtered and concentrated. The residue waspurified by normal phase chromatography and was eluted with hexanes andEtOAc to afford tert-butylN-[(1S)-1-[3-(4-amino-1-methyl-1H-pyrazol-5-yl)-5-fluorophenyl]but-3-en-1-yl]carbamate(0.105 g, 92%). MS(ESI) m/z: 361.08 (M+H)⁺.

41C. Preparation of tert-butylN-[(1S)-1-(3-fluoro-5-{1-methyl-4-[(2R)-2-methylbut-3-enamido]-1H-pyrazol-5-yl}phenyl)but-3-en-1-yl]carbamate

To tert-butylN-[(1S)-1-[3-(4-amino-1-methyl-1H-pyrazol-5-yl)-5-fluorophenyl]but-3-en-1-yl]carbamate(0.105 g, 0.291 mmol) was added EtOAc (0.6 ml), (R)-2-methylbut-3-enoicacid (0.035 g, 0.350 mmol), prepared as described in Intermediate 2, in0.3 ml EtOAc. The reaction mixture was cooled to 0° C., and a 50% EtOAcsolution of T3P® (0.347 ml, 0.583 mmol) and Hunig's Base (0.153 ml,0.874 mmol) were added. After 4 h, the reaction was partitioned betweensat NaHCO₃ (5 ml) and EtOAc (5 ml). The aqueous layer was extracted withEtOAc (2×10 ml). The combined organic layers were washed with brine (5ml), dried (MgSO₄), filtered and concentrated. The residue was purifiedby normal phase chromatography and was eluted with hexanes and EtOAc togive tert-butylN-[(1S)-1-(3-fluoro-5-{1-methyl-4-[(2R)-2-methylbut-3-enamido]-1H-pyrazol-5-yl}phenyl)but-3-en-1-yl]carbamateas a yellow foam (53 mg, 41%). MS(ESI) m/z: 443.5 (M+H)⁺.

41D. Preparation of tert-butylN-[(9R,10E,13S)-16-fluoro-3,9-dimethyl-8-oxo-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate

To a degassed DCE (10 ml) solution of tert-butylN-[(1S)-1-(3-fluoro-5-{1-methyl-4-[(2R)-2-methylbut-3-enamido]-1H-pyrazol-5-yl}phenyl)but-3-en-1-yl]carbamate(0.053 g, 0.120 mmol) was added Second Generation Grubbs Catalyst (0.041g, 0.048 mmol) and the reaction mixture was heated to 120° C. for 30 minin a microwave. The reaction mixture was directly purified by normalphase chromatography eluting with hexanes and EtOAc to afford tert-butylN-[(9R,10E,13S)-16-fluoro-3,9-dimethyl-8-oxo-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate as a dark solid (27 mg,54%). MS(ESI) m/z: 415.4 (M+H)⁺.

41E. Preparation of(9R,13S)-13-amino-16-fluoro-3,9-dimethyl-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

To an EtOH (3 ml) solution of tert-butylN-[(9R,10E,13S)-16-fluoro-3,9-dimethyl-8-oxo-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate (0.027 g, 0.065 mmol) wasadded PtO₂ (5 mg). The reaction mixture was purged with H₂ and was thenhydrogenated at 55 psi. After 6 h, the reaction mixture was filteredthrough CELITE® and concentrated to give 19 mg of a dark solid MS(ESI)m/z: 417.08 (M+H)⁺. The dark solid residue was dissolved in 50% TFA/DCM(3 ml). After 3 h, the reaction mixture was concentrated, the residuewas dissolved in DCM/MeOH, passed through a basic cartridge andconcentrated to give(9R,13S)-13-amino-16-fluoro-3,9-dimethyl-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onea dark solid (19 mg, 92%). MS(ESI) m/z: 317.4 (M+H)⁺.

Intermediate 42 Preparation of(9R,13S)-13-amino-3,9-dimethyl-3,4,7,17-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

42A. Preparation of tert-butylN-[(1S)-1-[2-(1-methyl-4-nitro-1H-pyrazol-5-yl)pyridin-4-yl]but-3-en-1-yl]carbamate

To a large microwave vial was added tert-butylN-[(1S)-1-(2-bromopyridin-4-yl) but-3-en-1-yl]carbamate (1.0 g, 3.06mmol), prepared as described in Intermediate 27,1-methyl-4-nitro-1H-pyrazole (0.427 g, 3.36 mmol), dioxane (10 ml),di(adamantan-1-yl)(butyl)phosphine (0.164 g, 0.458 mmol), K₂CO₃ (1.267g, 9.17 mmol) and pivalic acid (0.106 ml, 0.917 mmol). The reaction waspurged with Ar. Pd(OAc)₂ (0.069 g, 0.306 mmol) was added and thereaction was stirred at 100° C. After 4 h, heating was stopped and thereaction was stirred at rt for 72 h. The reaction was quenched withwater (20 ml) and extracted with EtOAc (3×50 ml). The combined organiclayers were washed with brine (20 ml), dried (MgSO₄), filtered, andconcentrated. The residue was purified by normal phase chromatographyusing heptanes and EtOAc as eluents to give tert-butylN-[(1S)-1-[2-(1-methyl-4-nitro-1H-pyrazol-5-yl)pyridin-4-yl]but-3-en-1-yl]carbamate (0.62 g, 54%) as a white foam.MS(ESI) m/z: 374.08 (M+H)⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.73 (d, J=5.2 Hz,1H), 8.28-8.15 (m, 1H), 7.66-7.54 (m, 1H), 7.43-7.34 (m, 1H), 5.76-5.63(m, 1H), 5.26-5.16 (m, 2H), 4.99 (br. s., 1H), 4.83 (br. s., 1H),3.97-3.85 (m, 3H), 2.66-2.46 (m, 2H), 1.45 (br. s., 9H).

42B. Preparation of tert-butylN-[(1S)-1-[2-(4-amino-1-methyl-1H-pyrazol-5-yl)pyridin-4-yl]but-3-en-1-yl]carbamate

To a cooled (0° C.) acetone (40 ml)/water (12 ml) solution of tert-butylN-[(1S)-1-[2-(1-methyl-4-nitro-1H-pyrazol-5-yl)pyridin-4-yl]but-3-en-1-yl]carbamate(0.62 g, 1.660 mmol) was added NH₄Cl (0.444 g, 8.30 mmol) and Zn (1.086g, 16.60 mmol). The ice bath was removed and the reaction was stirred 18h. The reaction was filtered through paper and partitioned with water(20 ml) and EtOAc (75 ml). The aqueous layer was extracted with EtOAc(2×50 ml). The combined organic layers were washed with brine (25 ml),dried (MgSO₄), filtered and concentrated. The residue was purified bynormal phase chromatography using DCM and 0-10% MeOH as eluents to givetert-butyl N-[(1S)-1-[2-(4-amino-1-methyl-1H-pyrazol-5-yl)pyridin-4-yl]but-3-en-1-yl]carbamate(0.46 g, 60%). MS(ESI) m/z: 344.5 (M+H)⁺.

42C. Preparation of tert-butylN-[(1S)-1-(2-{1-methyl-4-[(2R)-2-methylbut-3-enamido]-1H-pyrazol-5-yl}pyridin-4-yl)but-3-en-1-yl]carbamate

To tert-butylN-[(1S)-1-[2-(4-amino-1-methyl-1H-pyrazol-5-yl)pyridin-4-yl]but-3-en-1-yl]carbamate(0.6 g, 1.747 mmol) was added (R)-2-methylbut-3-enoic acid (0.189 g,1.893 mmol), prepared as described in Intermediate 2, in EtOAc (5.8 ml),cooled to 0° C. Pyridine (0.0.424 ml, 5.24 mmol) and a 50% EtOAcsolution of T3P® (2.080 ml, 3.49 mmol) were added. After 24 h, thereaction was partitioned between sat NaHCO₃ (10 ml) and EtOAc (20 ml).The aqueous layer was extracted with EtOAc (2×20 ml). The combinedorganic layers were washed with brine (10 ml), dried (MgSO₄), filteredand concentrated. The residue was purified by normal phasechromatography using hexanes and EtOAc as eluents to give tert-butylN-[(1S)-1-(2-{1-methyl-4-[(2R)-2-methylbut-3-enamido]-1H-pyrazol-5-yl}pyridin-4-yl)but-3-en-1-yl]carbamate(0.35 g, 47%). MS(ESI) m/z: 426.1 (M+H)⁺. ¹H NMR (500 MHz, CDCl₃) δ10.23 (br. s., 1H), 8.70-8.56 (m, 1H), 8.35 (d, J=1.1 Hz, 1H), 7.56-7.44(m, 1H), 7.25-7.14 (m, 1H), 6.03 (ddd, J=17.2, 10.2, 8.0 Hz, 1H),5.39-5.17 (m, 3H), 5.03-4.63 (m, 2H), 4.14-4.08 (m, 3H), 3.22 (quin,J=7.2 Hz, 1H), 2.66-2.49 (m, 1H), 1.84-1.72 (m, 1H), 1.50-1.40 (m, 9H),1.42-1.37 (m, 3H), 1.06-0.93 (m, 1H).

42D. Preparation of tert-butylN-[(9R,10E,13S)-3,9-dimethyl-8-oxo-3,4,7,17-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate

To a degassed DCE (20 ml) solution of tert-butylN-[(1S)-1-(2-{1-methyl-4-[(2R)-2-methylbut-3-enamido]-1H-pyrazol-5-yl}pyridin-4-yl)but-3-en-1-yl]carbamate(0.160 g, 0.376 mmol) was added Second Generation Grubbs Catalyst (0.096g, 0.113 mmol) and the reaction mixture was heated to 120° C. for 30 minin a microwave. The reaction mixture was concentrated and the residuewas purified by normal phase chromatography using DCM and MeOH aseluents to afford desired product (29 mg, 19%) as a green film. MS(ESI)m/z: 398.3 (M+H)⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.71 (d, J=4.7 Hz, 1H),7.58 (s, 1H), 7.23 (d, J=13.8 Hz, 1H), 7.03-6.94 (m, 1H), 6.61 (s, 1H),5.82-5.71 (m, 1H), 5.19-5.09 (m, 2H), 4.75 (br. s., 1H), 4.15-4.09 (m,3H), 3.19-3.10 (m, 1H), 2.67 (br. s., 1H), 2.28-2.15 (m, 2H), 1.54-1.39(m, 9H), 1.34-1.28 (m, 3H).

42E. Preparation of(9R,13S)-13-amino-3,9-dimethyl-3,4,7,17-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

To an EtOH (3 mL) solution of tert-butylN-[(9R,10E,13S)-3,9-dimethyl-8-oxo-3,4,7,17-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate(29 mg, 0.073 mmol) was added PtO₂ (4 mg). The reaction mixture waspurged with H₂, then was hydrogenated at 55 psi. After 3 h, the reactionmixture was filtered through a 0.45 M filter and concentrated to afforda dark solid (MS(ESI) m/z: 400.3 (M+H)⁺). The dark solid residue wasdissolved in 4 N HCl in dioxane (1 ml) and MeOH (1 ml). After 3 h, themixture was concentrated and resultant HCl salt was dissolved inDCM/MeOH and passed through a basic cartridge to afford(9R,13S)-13-amino-3,9-dimethyl-3,4,7,17-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-oneas a dark solid (21 mg, 96%). MS(ESI) m/z: 300.2 (M+H)⁺.

Intermediate 43 Preparation of(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,16-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

43A. Preparation of (S)-tert-butyl(1-(5-(1-(difluoromethyl)-4-nitro-1H-pyrazol-5-yl)pyridin-3-yl)but-3-en-1-yl)carbamate

To a large microwave vial was added (S)-tert-butyl(1-(5-bromopyridin-3-yl)but-3-en-1-yl)carbamate (1.0 g, 3.06 mmol),prepared a described in Intermediate 26,1-(difluoromethyl)-4-nitro-1H-pyrazole (0.548 g, 3.36 mmol), DMF (10.19ml), di(adamantan-1-yl)(butyl)phosphine (0.164 g, 0.458 mmol), K₂CO₃(1.267 g, 9.17 mmol) and pivalic acid (0.106 ml, 0.917 mmol). Thereaction mixture was purged with Ar. After 10 min, Pd(OAc)₂ (0.069 g,0.306 mmol) was added, the vessel sealed, and stirred at 115° C. After 4h, the reaction was quenched with H₂O (50 mL) and extracted with EtOAc(3×50 mL). The combined organic phase was washed with brine (50 mL),dried (MgSO₄), filtered, and concentrated. The crude material waspurified by normal phase chromatography eluting with a gradient ofheptane/EtOAc to give (S)-tert-butyl(1-(5-(1-(difluoromethyl)-4-nitro-1H-pyrazol-5-yl)pyridin-3-yl)but-3-en-1-yl)carbamate(1.25 g, 100%). MS(ESI) m/z: 410.2 (M+H)⁺.

43B. Preparation of (S)-tert-butyl(1-(5-(4-amino-1-(difluoromethyl)-1H-pyrazol-5-yl)pyridin-3-yl)but-3-en-1-yl)carbamate

(S)-tert-Butyl(1-(5-(1-(difluoromethyl)-4-nitro-1H-pyrazol-5-yl)pyridin-3-yl)but-3-en-1-yl)carbamate(1.27 g, 3.10 mmol) was dissolved in acetone (15 ml)/water (3 ml),cooled to 0° C., and NH₄Cl (0.830 g, 15.51 mmol) and Zn (2.028 g, 31.0mmol) were added. The ice bath was removed. After 2 h, the reactionmixture was filtered and filtrate partitioned with water (30 ml) andEtOAc (50 ml). The aqueous layer was extracted with EtOAc (2×50 ml). Thecombined organic phase was washed with brine (20 ml), dried (MgSO₄),filtered, and concentrated. The residue was purified by normal phasechromatography eluting with a gradient of DCM/MeOH to give(S)-tert-butyl(1-(5-(4-amino-1-(difluoromethyl)-1H-pyrazol-5-yl)pyridin-3-yl)but-3-en-1-yl)carbamate(0.720 g, 61.2% yield) as a solid. MS(ESI) m/z: 380 (M+H)⁺.

43C. Preparation of tert-butyl((S)-1-(5-(1-(difluoromethyl)-4-((R)-2-methylbut-3-enamido)-1H-pyrazol-5-yl)pyridin-3-yl)but-3-en-1-yl)carbamate

A solution of (S)-tert-butyl(1-(5-(4-amino-1-(difluoromethyl)-1H-pyrazol-5-yl)pyridin-3-yl)but-3-en-1-yl)carbamate(0.720 g, 1.898 mmol) in EtOAc (20 ml) was cooled to 0° C. and(R)-2-methylbut-3-enoic acid (0.228 g, 2.277 mmol), prepared asdescribed in Intermediate 2, in EtOAc (10 ml), pyridine (0.460 ml, 5.69mmol), and T3P® (50% wt in EtOAc) (2.259 ml, 3.80 mmol) were added.After 6 h, the reaction was partitioned with 1.5 M K₂P04 (50 mL) andEtOAc (50 mL). The aqueous layer was extracted with EtOAc (2×20 mL). Thecombined organic phase was washed with brine (50 mL), dried (MgSO₄),filtered, and concentrated. The residue was purified by normalchromatography eluting with a gradient of hexanes/EtOAc to givetert-butyl((S)-1-(5-(1-(difluoromethyl)-4-((R)-2-methylbut-3-enamido)-1H-pyrazol-5-yl)pyridin-3-yl)but-3-en-1-yl)carbamate(0.386 g, 44.1% yield) as a yellow foam. MS(ESI) m/z: 462.2 (M+H)⁺.

43D. Preparation of tert-butylN-[(9R,10E,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,16-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate

To a RBF was added tert-butyl((S)-1-(5-(1-(difluoromethyl)-4-((R)-2-methylbut-3-enamido)-1H-pyrazol-5-yl)pyridin-3-yl)but-3-en-1-yl)carbamate(0.190 g, 0.412 mmol), pTsOH (0.086 g, 0.453 mmol), and degassed DCE(103 ml). The clear yellow solution was warmed to 40° C. and degassedwith Ar for 1 h. Second Generation Grubbs Catalyst (0.140 g, 0.165 mmol)was added and reaction stirred at 40° C. overnight. Additional SecondGeneration Grubbs Catalyst (0.2 eq.) was added and stirring continued.After stirring for a total of 48 h, the reaction mixture was cooled tort, washed with sat NaHCO₃, brine, dried over MgSO₄, filtered, andconcentrated. The crude product was purified by normal phasechromatography eluting with a gradient of DCM/MeOH to give tert-butylN-[(9R,10E,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,16-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate(0.020 g, 11.2%) as a brown oil. MS(ESI) m/z: 434.3 (M+H)⁺.

43E. Preparation of tert-butylN-[(9R,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,16-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate

To an EtOH (3 mL) solution of tert-butylN-[(9R,10E,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,16-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate(0.020, 0.046 mmol) was added PtO₂ (1.048 mg, 4.61 μmol) and thereaction was purged with H₂. The reaction mixture was subjected to a H₂atmosphere (55 psi). After 2 h, the catalyst was filtered off through aplug of CELITE® and the filtrate concentrated to give tert-butylN-[(9R,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,16-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate.MS(ESI) m/z: 436.2 (M+H)⁺.

43F. Preparation of(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,16-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

tert-ButylN-[(9R,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,16-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate(0.020 g, 0.046 mmol) was dissolved in 4 N HCl in dioxane (0.230 ml,0.919 mmol). A minimum amount of MeOH was added to aid dissolution.After 1 h, the reaction mixture was concentrated to dryness. The residuewas dissolved in MeOH, passed through a NaHCO₃ cartridge (StratoSpheresSPE; 500 mg, 0.90 mmol loading), concentrated to give(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,16-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one.MS(ESI) m/z: 336.2 (M+H)⁺.

Intermediate 44 Preparation of 6-(2-bromo-5-chlorophenyl)pyrimidin-4-ol

44A. Preparation of 4-(2-bromo-5-chlorophenyl)-6-methoxypyrimidine

To a suspension of 4-chloro-2-(6-methoxypyrimidin-4-yl)aniline (100 mg,0.424 mmol) and TsOH.H₂O (97 mg, 0.509 mmol) in CH₃CN (20 mL) was addedCuBr₂ (9.48 mg, 0.042 mmol). Then t-butyl nitrite (0.067 mL, 0.509 mmol)was added followed by tetrabutylammonium bromide (274 mg, 0.849 mmol)and the reaction was stirred at rt. After 2 h, water was added and themixture was extracted with CH₂Cl₂ (2×). The organic layers werecombined, dried over MgSO₄, filtered, and concentrated. Purification bynormal phase chromatography gave4-(2-bromo-5-chlorophenyl)-6-methoxypyrimidine (115 mg, 90% yield) as awhite solid. MS(ESI) m/z: 299.2 (M+H)⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.88(d, J=1.1 Hz, 1H), 7.61 (d, J=8.6 Hz, 1H), 7.56 (d, J=2.6 Hz, 1H),7.30-7.24 (m, 1H), 7.04 (d, J=1.1 Hz, 1H), 4.05 (s, 3H).

44B. Preparation of 6-(2-bromo-5-chlorophenyl)pyrimidin-4-ol

6-(2-Bromo-5-chlorophenyl)pyrimidin-4-ol was prepared according to theprocedures described in Intermediate 5 for the synthesis of6-(5-chloro-2-fluorophenyl) pyrimidin-4-ol, by replacing6-(5-chloro-2-fluorophenyl)pyrimidin-4-ol with4-(2-bromo-5-chlorophenyl)-6-methoxypyrimidine. MS(ESI) m/z: 285.2(M+H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.19 (s, 1H), 7.72 (d, J=8.6 Hz,1H), 7.52 (d, J=2.6 Hz, 1H), 7.41 (dd, J=8.6, 2.6 Hz, 1H), 6.21 (s, 1H).

Example 45 Preparation of(9R,13S)-13-(4-{5-chloro-2-[(pyrimidin-2-yl)amino]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

(9R,13S)-13-(4-{5-Chloro-2-[(pyrimidin-2-yl)amino]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one,2 trifluoroacetate (2.75 mg, 19% yield) was prepared in a similar manneras the procedure described in Example 314, by replacing4-bromopyrimidine hydrochloride (6.78 mg, 0.035 mmol) with2-bromopyrimidine (5.51 mg, 0.035 mmol). MS(ESI) m/z: 582.5 (M+H)⁺. ¹HNMR (400 MHz, CD₃OD) δ 9.12 (s, 1H), 8.74 (d, J=5.1 Hz, 1H), 8.46-8.42(m, 3H), 7.73 (s, 1H), 7.66 (d, J=2.6 Hz, 1H), 7.54-7.48 (m, 2H), 7.43(dd, J=8.9, 2.5 Hz, 1H), 6.85 (t, J=5.0 Hz, 1H), 6.79 (s, 1H), 6.06 (dd,J=12.7, 4.3 Hz, 1H), 4.05 (s, 3H), 2.78-2.67 (m, 1H), 2.42-2.31 (m, 1H),2.16-2.02 (m, 2H), 1.69-1.44 (m, 2H), 1.02 (d, J=6.8 Hz, 3H), 0.80-0.63(m, 1H). Analytical HPLC (Method A): RT=8.33 min, 97.9% purity; FactorXIa Ki=2,000 nM.

Example 46 Preparation of ethyl2-[4-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)-1H-pyrazol-1-yl]acetate

Ethyl2-[4-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)-1H-pyrazol-1-yl]acetatetrifluoroacetate (3.67 mg, 15% yield) was prepared in a similar manneras the procedure described in Example 49, by replacing1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolewith ethyl2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)acetate(13.67 mg, 0.049 mmol). MS(ESI) m/z: 641.5 (M+H)⁺. ¹H NMR (400 MHz,CD₃OD) δ 8.96 (s, 1H), 8.74 (d, J=5.3 Hz, 1H), 7.72 (s, 1H), 7.62 (s,1H), 7.56-7.52 (m, 2H), 7.51-7.49 (m, 3H), 7.45 (s, 1H), 6.41 (s, 1H),6.00 (dd, J=12.7, 4.1 Hz, 1H), 4.94 (s, 2H), 4.18 (q, J=7.1 Hz, 2H),4.05 (s, 3H), 2.76-2.66 (m, 1H), 2.40-2.28 (m, 1H), 2.14-2.03 (m, 2H),1.67-1.42 (m, 2H), 1.24 (t, J=7.2 Hz, 3H), 1.02 (d, J=6.8 Hz, 3H),0.80-0.65 (m, 1H). Analytical HPLC (Method A): RT=7.92 min, 99.6%purity; Factor XIa Ki=25 nM, Plasma Kallikrein Ki=7,000 nM.

Example 47 Preparation of2-[4-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)-1H-pyrazol-1-yl]aceticacid

2-[4-(4-Chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)-1H-pyrazol-1-yl]aceticacid trifluoroacetate (8.6 mg, 35% yield) was also isolated from Example46. MS(ESI) m/z: 613.5 (M+H)⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.94 (s, 1H),8.75 (d, J=5.3 Hz, 1H), 7.74 (s, 1H), 7.60 (s, 1H), 7.56-7.48 (m, 5H),7.46 (s, 1H), 6.45 (d, J=0.4 Hz, 1H), 6.00 (dd, J=12.5, 4.2 Hz, 1H),4.90 (s, 2H), 4.05 (s, 3H), 2.75-2.66 (m, 1H), 2.33 (tt, J=12.7, 4.5 Hz,1H), 2.14-2.03 (m, 2H), 1.66-1.42 (m, 2H), 1.02 (d, J=6.8 Hz, 3H),0.82-0.66 (m, 1H). Analytical HPLC (Method A): RT=6.68 min, 99.0%purity; Factor XIa Ki=12 nM, Plasma Kallikrein Ki=6,000 nM.

Example 48 Preparation of2-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)acetonitrile

2-(4-Chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)acetonitriletrifluoroacetate (2.2 mg, 11% yield) was prepared in a similar manner asthe procedure described in Example 49, by replacing1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolewith 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (9.52 mg,0.049 mmol). MS(ESI) m/z: 528.35 (M+H)⁺. ¹H NMR (500 MHz, CD₃OD) δ 9.04(br. s., 1H), 8.74 (d, J=5.2 Hz, 1H), 7.73 (s, 1H), 7.59-7.49 (m, 5H),6.65 (s, 1H), 6.06 (d, J=9.6 Hz, 1H), 4.18-4.08 (m, 2H), 4.06 (s, 3H),2.78-2.68 (m, 1H), 2.42-2.33 (m, 1H), 2.16-2.03 (m, 2H), 1.68-1.58 (m,1H), 1.55-1.45 (m, 1H), 1.02 (d, J=6.9 Hz, 3H), 0.79-0.65 (m, 1H).Analytical HPLC (Method C): RT=1.46 min, 100% purity; Factor XIa Ki=16nM, Plasma Kallikrein Ki=850 nM.

Example 49 Preparation of(9R,13S)-13-{4-[5-chloro-2-(1-methyl-1H-pyrazol-4-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

To a degassed solution of(9R,13S)-13-[4-(5-chloro-2-iodophenyl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(15 mg, 0.024 mmol), prepared as described in Example 211,1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(7.61 mg, 0.037 mmol), and K₂CO₃ (8.43 mg, 0.061 mmol) in 1,4-dioxane(0.6 ml) and water (0.2 ml) was added Pd(Ph₃P)₄ (2.82 mg, 2.440 μmol).The reaction was microwaved at 120° C. for 0.5 h, and then cooled to rtand concentrated. Purification by reverse phase chromatography afforded(9R,13S)-13-{4-[5-chloro-2-(1-methyl-1H-pyrazol-4-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate (7.9 mg, 47% yield) as an off-white solid. MS(ESI) m/z:569.6 (M+H)⁺. ¹H NMR (500 MHz, CD₃OD) δ 8.97 (s, 1H), 8.75 (d, J=5.2 Hz,1H), 7.73 (s, 1H), 7.59 (s, 1H), 7.55-7.52 (m, 2H), 7.50-7.45 (m, 3H),7.33 (s, 1H), 6.40 (d, J=0.6 Hz, 1H), 6.02 (dd, J=12.7, 3.9 Hz, 1H),4.05 (s, 3H), 3.84 (s, 3H), 2.75-2.68 (m, 1H), 2.39-2.30 (m, 1H),2.13-2.02 (m, 2H), 1.66-1.45 (m, 2H), 1.02 (d, J=7.2 Hz, 3H), 0.78-0.65(m, 1H). Analytical HPLC (Method A): RT=7.01 min, 98.4% purity; FactorXIa Ki=14 nM, Plasma Kallikrein Ki=930 nM.

Example 50 Preparation of(9R,13S)-13-{4-[5-chloro-2-(1,3-dimethyl-1H-pyrazol-4-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate

(9R,13S)-13-{4-[5-Chloro-2-(1,3-dimethyl-1H-pyrazol-4-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate (11.3 mg, 49% yield) was prepared in a similar manneras the procedure described in Example 49, by replacing1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolewith1,3-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(10.84 mg, 0.049 mmol). MS(ESI) m/z: 583.5 (M+H)⁺. ¹H NMR (400 MHz,CD₃OD) δ 8.95 (s, 1H), 8.73 (d, J=5.1 Hz, 1H), 7.73-7.69 (m, 2H),7.55-7.47 (m, 4H), 7.33 (d, J=8.4 Hz, 1H), 6.24 (d, J=0.7 Hz, 1H), 5.97(dd, J=12.7, 4.3 Hz, 1H), 4.05 (s, 3H), 3.81 (s, 3H), 2.76-2.65 (m, 1H),2.39-2.28 (m, 1H), 2.13-1.97 (m, 2H), 1.90 (s, 3H), 1.66-1.42 (m, 2H),1.01 (d, J=6.8 Hz, 3H), 0.80-0.63 (m, 1H). Analytical HPLC (Method A):RT=7.15 min, 99.6% purity; Factor XIa Ki=270 nM, Plasma KallikreinKi=5,200 nM.

Example 51 Preparation of(10R,14S)-14-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-10-methyl-4,5,8-triazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-9-one

51A. Preparation of 5-bromopyridazin-4-amine

tert-Butyl N-(5-bromopyridazin-4-yl)carbamate (400 mg, 1.183 mmol) inDCM (15 mL) was added TFA (4.56 mL, 59.2 mmol). The reaction was stirredat rt overnight. Concentration gave5-bromopyridazin-4-amine.trifluoroacetate as a dark brownish solid.MS(ESI) m/z: 174.2 (M+H)⁺.

51B. Preparation of(10R,14S)-14-amino-10-methyl-4,5,8-triazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2,4,6,15,17-hexaen-9-one

(10R,14S)-14-Amino-10-methyl-4,5,8-triazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2,4,6,15,17-hexaen-9-onewas prepared in a similar manner as the procedure described inIntermediate 38, by replacing 2-bromopyridin-3-amine with5-bromopyridazin-4-amine. MS(ESI) m/z: 297.5 (M+H)⁺.

51C. Preparation of(10R,14S)-14-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-10-methyl-4,5,8-triazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-9-one

(10R,14S)-14-(4-{5-Chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-10-methyl-4,5,8-triazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-9-onetrifluoroacetate (3.8 mg, 32.7% yield) was prepared in a similar manneras the procedure described in Example 56 by using(10R,14S)-14-amino-10-methyl-4,5,8-triazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2,4,6,15,17-hexaen-9-one(4.5 mg, 0.015 mmol). ¹H NMR (400 MHz, CD₃OD) δ 9.42 (s, 1H), 9.14 (s,1H), 8.82-8.77 (m, 1H), 8.42 (s, 1H), 7.90-7.84 (m, 1H), 7.81 (s, 1H),7.77-7.72 (m, 1H), 7.70-7.65 (m, 1H), 7.65-7.61 (m, 2H), 7.30-7.24 (m,1H), 6.45 (d, J=0.7 Hz, 1H), 5.77 (dd, J=12.9, 4.3 Hz, 1H), 2.70-2.59(m, 1H), 2.36-2.23 (m, 1H), 2.13-2.00 (m, 1H), 2.00-1.89 (m, 1H),1.67-1.35 (m, 2H), 1.26-1.13 (m, 1H), 1.07 (d, J=6.8 Hz, 3H). MS(ESI)m/z: 621.0 (M+H)⁺. Analytical HPLC (Method A): RT=8.24 min, purity=100%;Factor XIa Ki=5 nM, Plasma Kallikrein Ki=18 nM.

Example 52 Preparation of1-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)-1H-pyrazole-4-carboxylicacid

To a solution of ethyl1-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)-1H-pyrazole-4-carboxylatetrifluoroacetate (7 mg, 0.011 mmol) in THF (56 μl) was added a solutionof LiOH.H₂O (4.7 mg, 0.112 mmol) in water (56 μl). To the resultingcloudy mixture was added MeOH (1 drop). The reaction was stirredvigorously at rt for 3.5 h. The solution was acidified to pH 5 with 1.0N HCl and then purified by reverse phase chromatography to give1-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)-1H-pyrazole-4-carboxylicacid trifluoroacetate (0.0024 g, 30% yield) as a white solid. MS(ESI)m/z: 599.1 (M+H)⁺. ¹H NMR (400 MHz, CD₃CN) δ 8.73-8.66 (m, 2H), 8.17 (s,1H), 7.94 (s, 1H), 7.81 (d, J=2.2 Hz, 1H), 7.73-7.62 (m, 3H), 7.61-7.55(m, 1H), 7.47-7.38 (m, 2H), 6.16 (d, J=0.9 Hz, 1H), 5.98 (dd, J=12.7,3.9 Hz, 1H), 4.02 (s, 3H), 2.65 (m, 1H), 2.30-2.19 (m, 1H), 2.15-2.02(m, 1H), 1.64-1.39 (m, 2H), 0.98 (d, J=6.8 Hz, 3H), 0.61 (m, 1H).Analytical HPLC (Method A): SunFire, RT=6.48 min, 99.3% purity; FactorXIa Ki=5 nM, Plasma Kallikrein Ki=2,400 nM.

Example 53 Preparation of(9R,13S)-13-[4-(2-bromo-5-chlorophenyl)-5-chloro-6-oxo-1,6-dihydropyrimidin-1-yl]-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

53A. Preparation of 6-(2-bromo-5-chlorophenyl)-5-chloropyrimidin-4-ol

To a suspension of 6-(2-bromo-5-chlorophenyl)pyrimidin-4-ol, prepared asdescribed in Intermediate 44, (40 mg, 0.140 mmol) in MeCN (1401 μl) wasadded NCS (20.58 mg, 0.154 mmol). The reaction was heated at 60° C. for4 h. The reaction mixture was concentrated and the crude residue waspurified using normal phase chromatography to yield6-(2-bromo-5-chlorophenyl)-5-chloropyrimidin-4-ol (42 mg, 94%) as awhite solid. MS(ESI) m/z: 320.9 (M+H)⁺.

53B. Preparation of(9R,13S)-13-[4-(2-bromo-5-chlorophenyl)-5-chloro-6-oxo-1,6-dihydropyrimidin-1-yl]-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

(9R,13S)-13-[4-(2-Bromo-5-chlorophenyl)-5-chloro-6-oxo-1,6-dihydropyrimidin-1-yl]-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate (8.3 mg, 41.1% yield) was prepared in a similar manneras the procedure described in Example 56, by using6-(2-bromo-5-chlorophenyl)-5-chloropyrimidin-4-ol (8.6 mg, 0.027 mmol)and(9R,13S)-13-amino-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(8 mg, 0.027 mmol), prepared as described in Intermediate 32. MS(ESI)m/z: 603.0 (M+H)⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.99 (s, 1H), 8.75 (d,J=5.1 Hz, 1H), 7.75 (s, 1H), 7.70 (d, J=8.6 Hz, 1H), 7.54 (dd, J=5.1,1.5 Hz, 1H), 7.50 (s, 1H), 7.45-7.38 (m, 2H), 6.06 (dd, J=12.4, 4.1 Hz,1H), 4.05 (s, 3H), 2.72 (td, J=6.7, 3.1 Hz, 1H), 2.45-2.31 (m, 1H),2.19-2.03 (m, 2H), 1.70-1.43 (m, 2H), 1.02 (d, J=7.0 Hz, 3H), 0.73 (br.s., 1H). Analytical HPLC (Method A): RT=9.24 min, 100% purity; FactorXIa Ki=8 nM, Plasma Kallikrein Ki=1,200 nM.

Example 54 Preparation of(9R,13S)-13-{4-[3-chloro-2-fluoro-6-(1,3-thiazol-5-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

54A. Preparation of4-(3-chloro-2-fluoro-6-iodophenyl)-6-methoxypyrimidine

4-Chloro-3-fluoro-2-(6-methoxypyrimidin-4-yl)aniline, prepared asdescribed in Intermediate 10C (1 g, 3.94 mmol) in ACN (26.3 ml) wascooled to 0° C. and pTsOH.H₂O (1.875 g, 9.86 mmol) was added followed byaddition of NaNO₂ (0.544 g, 7.88 mmol) and NaI (1.477 g, 9.86 mmol) inwater (13.14 ml). After 1 h, the reaction was warmed to rt and stirredovernight. After this time, the reaction was partially concentrated toremove the ACN and NaHCO₃ was then added to neutralize the solution. Theresulting solution was extracted with EtOAc. The combined organic layerwas washed with sat Na₂S₂O₃ and brine, dried over MgSO₄, filtered, andconcentrated to yield a solid, which was purified by normal phasechromatography to give4-(3-chloro-2-fluoro-6-iodophenyl)-6-methoxypyrimidine (0.934 g, 65%yield). MS(ESI) m/z: 365.2 (M+H)⁺.

54B. Preparation of 6-(3-chloro-2-fluoro-6-iodophenyl)pyrimidin-4-ol

6-(3-Chloro-2-fluoro-6-iodophenyl)pyrimidin-4-ol was prepared accordingto the procedures as described in Intermediate 4B for the synthesis of6-(3-chloro-2,6-difluorophenyl)pyrimidin-4-ol, by replacing4-(3-chloro-2,6-difluorophenyl)-6-methoxypyrimidine, prepared asdescribed in Intermediate 4A, with4-(3-chloro-2-fluoro-6-iodophenyl)-6-methoxypyrimidine. MS(ESI) m/z:350.8 (M+H)⁺.

54C. Preparation of(9R,13S)-13-[4-(3-chloro-2-fluoro-6-iodophenyl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

(9R,13S)-13-[4-(3-Chloro-2-fluoro-6-iodophenyl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onewas prepared in a similar manner as the procedure described in Example56, using 6-(3-chloro-2-fluoro-6-iodophenyl)pyrimidin-4-ol (62.7 mg,0.179 mmol) and(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(60 mg, 0.179 mmol), prepared as described in Intermediate 30. MS(ESI)m/z: 667.1 (M+H)⁺.

54D. Preparation of(9R,13S)-13-{4-[3-chloro-2-fluoro-6-(1,3-thiazol-5-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

To a microwave tube was added(9R,13S)-13-[4-(3-chloro-2-fluoro-6-iodophenyl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(20 mg, 0.030 mmol),5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazole (9.47 mg, 0.045mmol), K₃PO₄ (29.9 μl, 0.090 mmol) and THF (299 μl). The solution wasbubbled through with Ar for several min then (DtBPF)PdCl₂ (0.974 mg,1.495 μmol) was added. The reaction was sealed and heated at 90° C.overnight. The solution was cooled to rt and Ar was again bubbledthrough the solution for several minutes and additional5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazole (9.47 mg, 0.045mmol) and Pd(PPh₃)₄ (3.46 mg, 2.99 μmol) were added. The solution washeated in a microwave at 120° C. for 30 min. The solution was thenfiltered and the residue was purified by reverse phase chromatography togive(9R,13S)-13-{4-[3-chloro-2-fluoro-6-(1,3-thiazol-5-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(0.67 mg, 2.9%). ¹H NMR (400 MHz, CD₃OD) δ 9.02 (s, 1H), 8.95 (s, 1H),8.77 (d, J=5.1 Hz, 1H), 7.80 (s, 1H), 7.74 (s, 1H), 7.72-7.60 (m, 3H),7.59-7.50 (m, 2H), 7.46 (dd, J=8.4, 1.3 Hz, 1H), 6.55 (s, 1H), 6.05 (dd,J=12.9, 4.3 Hz, 1H), 2.71 (dt, J=6.6, 3.3 Hz, 1H), 2.40-2.26 (m, 1H),2.12-1.97 (m, 2H), 1.70-1.41 (m, 2H), 1.00 (d, J=7.0 Hz, 3H), 0.66 (br.s., 1H). MS(ESI) m/z: 625.9 (M+H)⁺. Analytical HPLC (Method A): RT=8.51min, purity=96.4%; Factor XIa Ki=1.7 nM, Plasma Kallikrein Ki=230 nM.

Example 55 Preparation of(9R,13S)-13-{4-[3-chloro-2-fluoro-6-(1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate

55A. Preparation of 1-methyl-4-nitro-1H-pyrazole

To a solution of 4-nitro-1H-pyrazole (2.5 g, 22.11 mmol) in THF (50 mL)was added NaH (0.973 g, 24.32 mmol) and the mixture was stirred at rtfor 5 min. To this suspension was added MeI (1.382 mL, 22.11 mmol) andthe resulting solution was stirred at rt overnight. The reaction mixturewas then diluted with EtOAc and washed with brine. The organic layer wasconcentrated, followed by purification using normal phase chromatographyto yield 1-methyl-4-nitro-1H-pyrazole as a white solid (1.9 g, 80%). ¹HNMR (400 MHz, CDCl₃) δ ppm 8.12 (s, 1H), 8.06 (s, 1H), 3.97 (s, 3H).

55B. Preparation of (S)-tert-butyl(1-(4-(1-methyl-4-nitro-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate

To a pressure vial was added (S)-tert-butyl1-(4-chloropyridin-2-yl)but-3-enylcarbamate, prepared as described inIntermediate 23, (3.0 g, 10.61 mmol), 1-methyl-4-nitro-1H-pyrazole(1.348 g, 10.61 mmol), di(adamant-1-yl)(butyl)phosphine (1.141 g, 3.18mmol), pivalic acid (0.369 mL, 3.18 mmol) and K₂CO₃ (4.40 g, 31.8 mmol).To the above mixture was added DMF (21 mL) and the vial was purged andevacuated (3×) with Ar. To this mixture was added Pd(OAc)₂ (0.476 g,2.122 mmol). The vial was sealed and heated at 120° C. overnight. Thereaction mixture was cooled to rt, filtered and partitioned between 10%aqueous LiCl (15 mL) and EtOAc (30 mL). The aqueous layer was extractedwith EtOAc (2×20 mL) and the combined organic layers were washed withbrine (15 mL), dried over MgSO₄, filtered and concentrated. The crudeproduct was then purified using normal phase chromatography to yield(S)-tert-butyl(1-(4-(1-methyl-4-nitro-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate(1.2 g, 29% yield) as a brown oil. MS(ESI) m/z: 374.4 (M+H)⁺.

55C. Preparation of (S)-tert-butyl(1-(4-(4-amino-1-methyl-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate

A solution of (S)-tert-butyl(1-(4-(1-methyl-4-nitro-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate(1.2 g, 3.21 mmol) in MeOH (10 mL) and CH₃COOH (1 ml) was heated to 60°C. To the above clear solution was then slowly added Zn (0.420 g, 6.43mmol) and the solution was allowed to stir at 60° C. for an additional15 min. The reaction mixture was then filtered through CELITE® andconcentrated to yield crude product. The crude product was then purifiedusing normal phase chromatography to yield (S)-tert-butyl(1-(4-(4-amino-1-methyl-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate(0.88 g, 76% yield) as a pale brown oil. MS(ESI) m/z: 344.4 (M+H)⁺.

55D. Preparation of tert-butyl((S)-1-(4-(1-methyl-4-((R)-2-methylbut-3-enamido)-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate

To a solution of(R)-4-benzyl-3-((R)-2-methylbut-3-enoyl)oxazolidin-2-one (385 mg, 3.84mmol), prepared as described in Intermediate 2A, (S)-tert-butyl(1-(4-(4-amino-1-methyl-H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate(880 mg, 2.56 mmol) and pyridine (0.620 mL, 7.69 mmol) in EtOAc (40 mL)at −10° C. under Ar was added T3P® (50% wt in EtOAc) (3.05 mL, 5.12mmol) dropwise. The reaction mixture was stirred at −10° C. and wasallowed to gradually warm up to rt. The reaction mixture was stirred atrt for 2 h, then diluted with EtOAc and washed with sat aq NaHCO₃ andbrine. The organic layers were pooled together, dried over MgSO₄,filtered and concentrated. The crude product was then purified usingnormal phase chromatography to yield tert-butyl((S)-1-(4-(1-methyl-4-((R)-2-methylbut-3-enamido)-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate(0.6 g, 52% yield) as a yellow oil. MS(ESI) m/z: 426.5 (M+H)⁺.

55E. Preparation of tert-butylN-[(9R,10E,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate

A solution of tert-butyl((S)-1-(4-(1-methyl-4-((R)-2-methylbut-3-enamido)-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate(600 mg, 1.410 mmol) in DCE (18 mL) was purged with Ar (3×). SecondGeneration Grubbs Catalyst (480 mg, 0.564 mmol) was added and Ar wasagain bubbled into the reaction mixture and evacuated (3×). The reactionmixture was then heated at 120° C. in a microwave vial for 30 min. Thereaction mixture was then concentrated and the crude residue waspurified using normal phase chromatography to yield tert-butylN-[(9R,10E,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate(118 mg, 20% yield) as a brown oil. MS(ESI) m/z: 398.5 (M+H)⁺.

55F. Preparation of tert-butylN-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate

To a degassed solution of tert-butylN-[(9R,10E,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate(118 mg, 0.297 mmol) in EtOH (12 mL) was added Pd/C (31.6 mg, 0.030mmol) and the reaction mixture was then stirred under H₂ at 55 psi for 5h. The reaction mixture was then filtered though CELITE® andconcentrated to yield tert-butylN-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate.(92 mg, 72%) as a brown oil. MS(ESI) m/z: 400.4 (M+H)⁺.

55G. Preparation of(9R,13S)-13-amino-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one,dihydrochloride

To a solution of tert-butylN-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate(92 mg, 0.230 mmol) in MeOH (3 mL) was added 4 M HCl in dioxane (3 mL,12 mmol) and the reaction was stirred at rt for 1.5 h. The reactionmixture was concentrated to yield(9R,13S)-13-amino-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onedihydrochloride (86 mg) as yellow solid. MS(ESI) m/z: 300.4 (M+H)⁺.

55H. Preparation of(9R,13S)-13-{4-[3-chloro-2-fluoro-6-(1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate

(9R,13S)-13-{4-[3-Chloro-2-fluoro-6-(1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate was prepared according to the procedure described inExample 56, by using(9R,13S)-13-amino-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onedihydrochloride and6-(3-chloro-2-fluoro-6-(1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol,prepared as described in Intermediate 7. MS(ESI) m/z: 574.3 (M+H)⁺. ¹HNMR (400 MHz, CD₃OD) δ 8.82 (s, 1H), 8.73 (d, J=5.3 Hz, 1H), 8.19 (d,J=1.1 Hz, 1H), 7.85 (dd, J=8.6, 7.7 Hz, 1H), 7.78 (d, J=1.1 Hz, 1H),7.70 (s, 1H), 7.56-7.50 (m, 2H), 7.49 (s, 1H), 6.53 (s, 1H), 5.98 (dd,J=12.8, 4.2 Hz, 1H), 4.05 (s, 3H), 2.70 (td, J=6.7, 3.2 Hz, 1H), 2.27(ddt, J=12.7, 8.5, 4.3 Hz, 1H), 2.14-1.92 (m, 2H), 1.66-1.53 (m, 1H),1.46 (ddd, J=15.1, 10.0, 5.3 Hz, 1H), 1.00 (d, J=7.0 Hz, 3H), 0.68 (m.,1H). Analytical HPLC (method A): RT=6.41 min, purity=93%; Factor XIaKi=1.0 nM, Plasma Kallikrein Ki=24 nM.

Example 56 Preparation of(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate

To a scintillation vial containing6-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}pyrimidin-4-ol(22.8 mg, 0.067 mmol), prepared as described in Intermediate 15, HATU(33.0 mg, 0.087 mmol) in anhydrous ACN (0.5 mL) was added DBU (15 mL,0.100 mmol). After 30 min, a solution of(9R,13S)-13-amino-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(20 mg, 0.067 mmol), prepared as described in Intermediate 32, in 0.5 mlCH₃CN and DMF (0.1 ml) was added. The resulting solution was stirred atrt for 2 h then purified by reverse phase chromatography to give(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate (26.98 mg, 53.1% yield) as a white solid. MS(ESI) m/z:624.3 (M+H)⁺. ¹H NMR (400 MHz, CD₃OD) d 8.81 (d, J=0.7 Hz, 1H), 8.75 (s,1H), 8.70 (d, J=5.3 Hz, 1H), 7.89 (d, J=2.4 Hz, 1H), 7.77-7.72 (m, 1H),7.72-7.66 (m, 2H), 7.53 (dd, J=5.1, 1.5 Hz, 1H), 7.49 (s, 1H), 6.43 (s,1H), 6.02-5.93 (m, 1H), 4.04 (s, 3H), 2.70 (td, J=6.7, 3.3 Hz, 1H), 2.27(tt, J=12.7, 4.4 Hz, 1H), 2.12-1.94 (m, 2H), 1.66-1.52 (m, 1H), 1.45(ddd, J=15.0, 9.8, 5.0 Hz, 1H), 1.00 (d, J=7.0 Hz, 3H), 0.69 (br. s.,1H). ¹⁹F NMR (376 MHz, CD₃OD) d −62.54 (s), −77.44 (s). Analytical HPLC(Method A): RT=11.02 min, purity=96.7%; Factor XIa Ki=1.4 nM, PlasmaKallikrein Ki=24 nM.

Example 57 Preparation of(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-9-ethyl-3-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate

57A. Preparation of 2-ethylbut-3-enoic acid

To a dry flask was added 2 M DIA in THF (8.28 mL, 58.1 mmol) and THF (50mL). The reaction was cooled to −78° C. and 1.6 M nBuLi in hexanes(23.23 mL, 58.1 mmol) was added dropwise. The reaction was stirred at−78° C. for 30 min. But-3-enoic acid (2.00 g, 23.23 mmol) was added tothe reaction and the reaction was stirred at −78° C. for 30 min. Afterthis time, EtI (5.44 g, 34.8 mmol) was added. The reaction was slowlywarmed to rt and stirred at rt overnight. The reaction was then quenchedwith sat NH₄Cl (3 mL). The pH of the reaction was adjusted to <4 using 1N HCl. The reaction was then extracted with EtOAc (2×30 mL). Thecombined organic layer was washed with water (20 mL) and brine (20 mL),dried over MgSO₄, filtered and concentrated. The residue was purifiedusing ISCO system (0-60% EtOAc/Hex gradient) to give 2-ethylbut-3-enoicacid (450 mg, 2.37 mmol, 10.2% yield) as a clear liquid. ¹H NMR (400MHz, CDCl₃) δ 5.89-5.75 (m, 1H), 5.22-5.18 (m, 1H), 5.16 (s, 1H), 2.95(q, J=7.5 Hz, 1H), 1.83 (dt, J=13.9, 7.2 Hz, 1H), 1.61 (dt, J=13.6, 7.4Hz, 1H), 0.95 (t, J=7.4 Hz, 3H).

57B. Preparation of tert-butyl((1S)-1-(4-(4-(2-ethylbut-3-enamido)-1-methyl-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate

To a RBF was added (S)-tert-butyl(1-(4-(4-amino-1-methyl-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate,prepared as described in Intermediate 32C, (1000 mg, 2.91 mmol), EtOAc(20 mL), 2-ethylbut-3-enoic acid (332 mg, 2.91 mmol), and pyridine (0.71mL, 8.74 mmol). The solution was cooled in a brine/ice bath and 50% T3P®(2.60 mL, 4.37 mmol) was added. The reaction was stirred at 0° C. for 10min and then at rt for 60 min. The reaction was diluted with EtOAc (30mL) and washed with sat NaHCO₃ (20 mL), water (30 mL) and brine (30 mL).The organic layer was separated, dried over MgSO₄, filtered andconcentrated. The residue was purified using ISCO system (0-100%EtOAc/Hex gradient) to give tert-butyl((1S)-1-(4-(4-(2-ethylbut-3-enamido)-1-methyl-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate(1.10 g, 2.50 mmol, 86% yield) as a diastereomer mixture as a yellowsolid. MS(ESI) m/z: 440.0 (M+H)⁺.

57C. Preparation of tert-butylN-[(9R,10E,13S)-9-ethyl-3-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate

To a microwave vial was added tert-butyl((1S)-1-(4-(4-(2-ethylbut-3-enamido)-1-methyl-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate(500 mg, 1.138 mmol) and DCE (12 mL). The reaction was purged with Arfor 1 min. Then Second Generation Grubbs Catalyst (386 mg, 0.455 mmol)was added to the solution. The reaction was sealed and heated inmicrowave at 120° C. for 30 min. The reaction was concentrated and theresidue was purified using ISCO system (0-10% MeOH/CH₂Cl₂ gradient). Twoproducts were isolated. The fast eluting product was tert-butylN-[(9R,10E)-9-ethyl-3-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate(75 mg, 0.182 mmol, 16.0% yield), MS(ESI) m/z: 412.2 (M+H)⁺ which wascarried forward and the slow eluting product was the other diastereomer,tert-butylN-[(9S,10E)-9-ethyl-3-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate(75 mg, 0.182 mmol, 16.0% yield), MS(ESI) m/z: 412.2 (M+H)⁺.

57D. Preparation of tert-butylN-[(9R,13S)-9-ethyl-3-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate

To a 3-neck RBF was added tert-butylN-[(9R,10E)-9-ethyl-3-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate(115 mg, 0.279 mmol), EtOH (10 mL) and PtO₂ (31.7 mg, 0.140 mmol). Thereaction was stirred under a H₂ atmosphere (balloon pressure) for 1 h.The reaction was carefully filtered through CELITE® and concentrated.The residue was purified using ISCO system (0-10% MeOH/CH₂Cl₂ gradient)to give tert-butylN-[(9R,13S)-9-ethyl-3-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate(75 mg, 0.181 mmol, 64.9% yield) as a light brown solid. MS(ESI) m/z:414.2 (M+H)⁺.

57E. Preparation of(9R,13S)-13-amino-9-ethyl-3-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

To a RBF was added tert-butylN-[(9R,13S)-9-ethyl-3-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate(75 mg, 0.181 mmol), dioxane (3 mL), 4 N HCl (18.14 mmol) and MeOH (0.5mL). The reaction was stirred at rt for 5 min. The reaction wasconcentrated and the residue was purified using reverse phasepreparative HPLC to give(9R,13S)-13-amino-9-ethyl-3-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one,trihydrochloride. The product was dissolved in MeOH (1 mL) to give aclear, brown solution. The solution was added to a pre-rinsed AGILENT®StratoSpheres SPE PL-HCO₃ MP Resin cartridge. Gravity filtration,eluting with MeOH, gave a clear, slightly brown filtrate. Concentrationprovided(9R,13S)-13-amino-9-ethyl-3-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(75 mg, 0.177 mmol, 98% yield) as a beige solid. MS(ESI) m/z: 314.2(M+H)⁺.

57F. Preparation of(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-9-ethyl-3-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate

(9R,13S)-13-{4-[5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-9-ethyl-3-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate (5 mg, 6.82 μmol, 26.3% yield) was prepared in asimilar manner as the procedure described in Example 56 by using6-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol (8mg, 0.026 mmol), prepared as described in Intermediate 9, and(9R)-13-amino-9-ethyl-3-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(8 mg, 0.026 mmol). ¹H NMR (400 MHz, CD₃OD) δ 8.87 (s, 1H), 8.72 (d,J=5.1 Hz, 1H), 7.89 (s, 1H), 7.76 (d, J=2.4 Hz, 1H), 7.64 (dd, J=8.5,2.3 Hz, 1H), 7.59 (s, 1H), 7.52 (d, J=8.6 Hz, 1H), 7.46 (s, 1H), 7.36(dd, J=5.1, 1.5 Hz, 1H), 6.37 (s, 1H), 6.06 (dd, J=12.5, 4.6 Hz, 1H),4.03 (s, 3H), 2.46-2.36 (m, 1H), 2.26-2.12 (m, 1H), 2.03-1.92 (m, 2H),1.69-1.56 (m, 2H), 1.45 (d, J=4.8 Hz, 1H), 1.32-1.20 (m, 1H), 0.86 (t,J=7.4 Hz, 3H), 0.69-0.57 (m, 1H); MS(ESI) m/z: 604.2 (M+H)⁺. AnalyticalHPLC (Method A): RT=7.23 min, purity=97.0%; Factor XIa Ki=0.36 nM,Plasma Kallikrein Ki=37 nM.

Example 58 Preparation of(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-methyl-9-(propan-2-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate

58A. Preparation of 2-isopropylbut-3-enoic acid

To a flame-dry RBF was added 2 M DIA in THF (3.64 ml, 25.6 mmol) and THF(58.1 ml). The reaction was cooled to −78° C. and 1.6 M nBuLi in hexane(15.97 ml, 25.6 mmol) was added. The reaction was stirred at −78° C. for30 min. But-3-enoic acid (0.990 ml, 11.62 mmol) was added and thereaction was stirred for additional 30 min. Then at −78° C., iPrI (1.74ml, 17.42 mmol) was added and the reaction was slowly warmed to rt over2 h and then stirred at rt overnight. The reaction was quenched with satNH₄Cl (15 ml). The pH of the solution was adjusted to <4 using 1 N HCl.The reaction was extracted with EtOAc (3×30 mL). The combined EtOAclayer was washed with brine (40 mL), dried over MgSO₄, filtered andconcentrated. The residue was purified using ISCO system (0-50%EtOAc/Hex gradient) to give 2-isopropylbut-3-enoic acid (800 mg, 6.24mmol, 53.7% yield) as a clear liquid. ¹H NMR (400 MHz, CDCl₃) δ5.98-5.65 (m, 1H), 5.33-5.05 (m, 2H), 2.73 (t, J=8.8 Hz, 1H), 2.08-1.95(m, 1H), 1.09-0.74 (m, 6H).

58B. Preparation of tert-butyl((1S-[1-(4-{1-methyl-4-[2-(propan-2-yl)but-3-enamido]-1H-pyrazol-5-yl}pyridin-2-yl)but-3-en-1-yl]carbamate

To a RBF was added (S)-tert-butyl(1-(4-(4-amino-1-methyl-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate,prepared as described in Intermediate 32C, (765 mg, 2.228 mmol), EtOAc(20 mL), 2-isopropylbut-3-enoic acid (286 mg, 2.228 mmol), and pyridine(0.540 mL, 6.68 mmol). The solution was cooled in a brine/ice bath and50% T3P® (1.989 mL, 3.34 mmol) was added. The reaction was stirred at 0°C. for 10 min and then at rt for 60 min. Reaction was diluted with EtOAc(30 mL) and washed with sat NaHCO₃ (20 mL), water (30 mL) and brine (30mL). The organic layer was separated, dried over MgSO₄, filtered andconcentrated. The residue was purified using ISCO system (0-100%EtOAc/Hex gradient) to give tert-butyl((1S)-1-(4-(4-(2-isopropylbut-3-enamido)-1-methyl-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate(850 mg, 1.874 mmol, 84% yield) as a diastereomer mixture as a yellowsolid. MS(ESI) m/z: 454.2 (M+H)⁺.

58C₁ and 58C₂. Preparation of tert-butylN-[(9S,10E,13S)-3-methyl-8-oxo-9-(propan-2-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate,and tert-butyl N-[(9R,10E,13S)-3-methyl-8-oxo-9-(propan-2-yl)-3,4,7,15tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate

To a microwave vial was added tert-butyl((1S)-1-(4-(4-(2-isopropylbut-3-enamido)-1-methyl-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate(250 mg, 0.551 mmol) and DCE (15 mL). The reaction was purged with Arfor 1 min. Then Second Generation Grubbs Catalyst (187 mg, 0.220 mmol)was added. The reaction was sealed and heated at microwave at 120° C.for 60 min. The reaction was then concentrated and the residue waspurified using reverse phase preparative HPLC to give 58C1, tert-butylN-[(9S,10E,13S)-3-methyl-8-oxo-9-(propan-2-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamatetrifluoroacetate (50 mg, 0.093 mmol, 16.8% yield), (ESI) m/z: 426.2(M+H)⁺, which has a shorter retention time and 58C₂, tert-butylN-[(9R,10E,13S)-3-methyl-8-oxo-9-(propan-2-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamatetrifluoroacetate (50 mg, 0.093 mmol, 16.8% yield), MS(ESI) m/z: 426.2(M+H)⁺ which had a longer retention time.

58D. Preparation of tert-butylN-[(9R,13S)-3-methyl-8-oxo-9-(propan-2-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate

To a 3-neck RBF was added tert-butylN-[(9S,10E,13S)-3-methyl-8-oxo-9-(propan-2-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamatetrifluoroacetate (20 mg, 0.037 mmol), EtOH (3 mL) and PtO₂ (4.21 mg,0.019 mmol). The reaction was stirred under a H₂ atmosphere (balloonpressure) for 1 h. The reaction was carefully filtered through CELITE®and the filtrate was concentrated to give tert-butylN-[(9R,13S)-3-methyl-8-oxo-9-(propan-2-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate(12 mg, 0.028 mmol, 76% yield). MS(ESI) m/z: 428.2 (M+H)⁺.

58E. Preparation of(9R,13S)-13-amino-3-methyl-9-(propan-2-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

To a round RBF flask was added tert-butylN-[(9R,13S)-3-methyl-8-oxo-9-(propan-2-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate(20 mg, 0.047 mmol), dioxane (3 mL), 4 N HCl in dioxane (0.14 mL, 4.68mmol) and MeOH (0.5 mL). The reaction was stirred at rt for 5 min. Thereaction was concentrated and the residue was purified using reversephase preparative HPLC to give(9R,13S)-13-amino-3-methyl-9-(propan-2-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onehydrochloride. The product was added to a pre-rinsed AGILENT®StratoSpheres SPE PL-HCO₃ MP Resin cartridge. Gravity filtration,eluting with MeOH, gave a clear, slightly brown filtrate. Concentrationprovided(9R,13S)-13-amino-3-methyl-9-(propan-2-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(7 mg, 0.016 mmol, 34.3% yield) as a solid. MS(ESI) m/z: 328.2 (M+H)⁺.

58F. Preparation of(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-methyl-9-(propan-2-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate

(9R,13S)-13-{4-[5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-methyl-9-(propan-2-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate (6 mg, 8.03 μmol, 40.4% yield) was prepared in asimilar manner as the procedure described in Example 56 by using6-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol(6.12 mg, 0.020 mmol), prepared as described in Intermediate 9, and(9R,13S)-13-amino-3-methyl-9-(propan-2-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(6.5 mg, 0.020 mmol). ¹H NMR (400 MHz, CD₃OD) δ 8.75 (s, 1H), 8.69 (d,J=5.1 Hz, 1H), 8.07-8.01 (m, 1H), 7.82-7.78 (m, 1H), 7.71-7.66 (m, 1H),7.65 (s, 1H), 7.60-7.57 (m, 1H), 7.52-7.47 (m, 1H), 7.36 (dd, J=5.1, 1.5Hz, 1H), 6.41 (d, J=0.7 Hz, 1H), 6.09 (dd, J=12.4, 4.3 Hz, 1H), 4.04 (s,3H), 2.16 (tt, J=12.6, 4.2 Hz, 1H), 2.06-1.71 (m, 5H), 1.60-1.48 (m,1H), 1.03 (dd, J=6.4, 3.7 Hz, 6H), 0.82 (q, J=11.4 Hz, 1H); MS(ESI) m/z:618.2 (M+H)⁺. Analytical HPLC (Method A): RT=11.50 min, purity=98.0%;Factor XIa Ki=56 nM, Plasma Kallikrein Ki=3,300 nM.

Example 59(9S,13S)-13-{4-[5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-methyl-9-(propan-2-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate

59A. Preparation of tert-butylN-[(9S,13S)-3-methyl-8-oxo-9-(propan-2-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate

To a 3-neck RBF was added tert-butylN-[(9R,10E,13S)-3-methyl-8-oxo-9-(propan-2-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamatetrifluoroacetate (15 mg, 0.028 mmol), prepared as described in Example58C₂, EtOH (3 mL) and PtO₂ (3.16 mg, 0.014 mmol). The reaction wasstirred under a H₂ atmosphere (balloon pressure) for 1 h. The reactionwas carefully filtered through CELITE® and the filtrate was concentratedto give tert-butylN-[(9S,13S)-3-methyl-8-oxo-9-(propan-2-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate(10 mg, 0.023 mmol, 84% yield) as a brown solid. MS(ESI) m/z: 618.2(M+H)⁺.

59B. Preparation of(9S,13S)-13-amino-3-methyl-9-(propan-2-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

To a RBF was added tert-butylN-[(9S,13S)-3-methyl-8-oxo-9-(propan-2-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate(20 mg, 0.047 mmol), dioxane (3 mL), 4 N HCl in dioxane (0.142 mL, 4.68mmol) and MeOH (0.5 mL). The reaction was stirred at rt for 5 min. Thereaction was concentrated and the residue was purified using reversephase preparative HPLC to give(9S,13S)-13-amino-3-methyl-9-(propan-2-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onehydrochloride. The product was added to a pre-rinsed AGILENT®StratoSpheres SPE PL-HCO₃ MP Resin cartridge. Gravity filtration,eluting with MeOH, gave a clear, slightly brown filtrate. Concentrationprovided(9S,13S)-13-amino-3-methyl-9-(propan-2-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(1.5 mg, 3.43 μmol, 7.34% yield) as a beige solid. MS(ESI) m/z: 328.2(M+H)⁺.

59C. Preparation of(9S,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-methyl-9-(propan-2-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate

(9S,13S)-13-{4-[5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-methyl-9-(propan-2-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate (0.6 mg, 0.778 μmol, 21.23% yield) was prepared in asimilar manner as the procedure described in Example 56 by using6-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol(1.129 mg, 3.66 μmol), prepared as described in Intermediate 9, and(9S,13S)-13-amino-3-methyl-9-(propan-2-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(1.2 mg, 3.66 μmol). ¹H NMR (400 MHz, CD₃OD) δ 8.80 (s, 1H), 8.76 (d,J=5.1 Hz, 1H), 8.38-8.36 (m, 1H), 7.92 (d, J=2.2 Hz, 1H), 7.79-7.75 (m,1H), 7.73 (s, 1H), 7.70-7.65 (m, 1H), 7.55 (dd, J=5.1, 1.5 Hz, 1H), 7.52(s, 1H), 6.40 (s, 1H), 5.98 (d, J=9.2 Hz, 1H), 4.08 (s, 3H), 2.46-2.27(m, 2H), 2.17-2.01 (m, 3H), 1.87-1.67 (m, 3H), 1.43 (br. s., 1H), 0.97(d, J=6.6 Hz, 3H), 0.92 (d, J=6.4 Hz, 3H); MS(ESI) m/z: 618.2 (M+H)⁺.Analytical HPLC (Method A): RT=11.52 min, purity=95.0%; Factor XIaKi=3.5 nM, Plasma Kallikrein Ki=370 nM.

Example 60 Preparation of(9S,13S)-13-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-methyl-9-(propan-2-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate

(9S,13S)-13-{4-[3-Chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-methyl-9-(propan-2-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate (0.8 mg, 1.013 mol, 3.32% yield) was prepared in asimilar manner as the procedure described in Example 56 by using6-(3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl)pyrimidin-4-ol (12.43 mg, 0.031 mmol) prepared as described inIntermediate 10 and

(9S,13S)-13-amino-3-methyl-9-(propan-2-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(10 mg, 0.031 mmol). ¹H NMR (400 MHz, CD₃OD) δ 8.80 (s, 1H), 8.75 (d,J=5.1 Hz, 1H), 8.27 (s, 1H), 7.87-7.83 (m, 1H), 7.69 (s, 1H), 7.56-7.49(m, 2H), 7.48 (s, 1H), 6.61 (s, 1H), 6.01 (d, J=8.8 Hz, 1H), 4.06 (s,3H), 2.33-2.24 (m, 1H), 2.13-1.99 (m, 3H), 2.14-1.97 (m, 4H), 1.83-1.69(m, 2H), 1.42 (br. s., 1H), 1.33-1.23 (m, 1H), 0.94 (d, J=6.8 Hz, 3H),0.89 (d, J=6.4 Hz, 3H); MS(ESI) m/z: 636.2 (M+H)⁺. Analytical HPLC(Method A): RT=11.266 min, purity=95.0%; Factor XIa Ki=0.53 nM, PlasmaKallikrein Ki=40 nM.

Example 61 Preparation of(9R,13S)-13-{4-[3-chloro-6-(difluoromethyl)-2-fluorophenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate

61A. Preparation of2-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

To a dry RBF was added 1-chloro-4-(difluoromethyl)-2-fluorobenzene (180mg, 0.997 mmol) and THF (3 mL). The reaction was cooled to −78° C. and 2M LDA in THF (0.498 mL, 0.997 mmol) was added dropwise. The reactionturned to dark red immediately after the addition. The reaction wasstirred at −78° C. for 5 min and2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (371 mg, 1.994mmol) was added in one portion. The reaction was stirred at −78° C. for20 min. The colored changed to pale yellow. The reaction was partitionedbetween EtOAc (30 mL) and water (20 mL). The organic layer wasseparated, washed with water (20 mL) and brine (20 mL), dried overMgSO₄, filtered and concentrated. The residue was purified using ISCOsystem (0-30% EtOAc/Hex gradient) to give2-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(125 mg, 0.408 mmol, 40.9% yield) as a light brown oil. ¹H NMR (400 MHz,CDCl₃) δ 7.45 (t, J=7.8 Hz, 1H), 7.29 (d, J=8.4 Hz, 1H), 7.10-6.74 (m,1H), 1.31 (s, 12H).

61B. Preparation of4-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-6-methoxypyrimidine

To a microwave vial was added2-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(120 mg, 0.391 mmol), 4-chloro-6-methoxypyrimidine (56.6 mg, 0.391mmol), toluene (2 mL), EtOH (1 mL) and 2 M Na₂CO₃ (0.587 mL, 1.174mmol). The reaction was purged with Ar and Pd(PPh₃)₄ (45 mg, 0.039 mmol)was added. The reaction was sealed and stirred in a microwave at 120° C.for 1 h. The reaction was partitioned between EtOAc (20 mL) and water(20 mL). The organic layer was separated, washed with water (10 mL) andbrine (15 mL), dried over MgSO₄, filtered and concentrated. The residuewas purified using ISCO system (0-30% EtOAc/Hex gradient) to give4-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-6-methoxypyrimidine (40mg, 0.139 mmol, 35.4% yield) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ8.88 (d, J=0.9 Hz, 1H), 7.64-7.57 (m, 1H), 7.56-7.50 (m, 1H), 7.11-6.76(m, 2H), 4.06 (s, 3H).

61C. Preparation of 6-(3-chloro-6-(difluoromethyl)-2fluorophenyl)pyrimidin-4-ol

To a RBF was added4-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-6-methoxypyrimidine (40mg, 0.139 mmol), AcOH (0.5 mL) and 48% HBr (0.784 mL, 6.93 mmol). Thereaction was stirred at 85° C. for 45 min. Then toluene (25 mL) wasadded and the reaction was concentrated. The residue was thenpartitioned between EtOAc (25 mL) and sat aq NaHCO₃ (25 mL). The organiclayer was separated, washed with water (15 mL) and brine (15 mL), driedover MgSO₄, filtered and concentrated. The residue was purified usingISCO system (0-100% EtOAc/Hex gradient) to give6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)pyrimidin-4-ol (36 mg,0.131 mmol, 95% yield) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 13.25(br. s., 1H), 8.28 (s, 1H), 7.70-7.57 (m, 1H), 7.53 (d, J=8.4 Hz, 1H),7.16-6.79 (m, 1H), 6.72 (br. s., 1H).

61D. Preparation of(9R,13S)-13-{4-[3-chloro-6-(difluoromethyl)-2-fluorophenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate

(9R,13S)-13-{4-[3-Chloro-6-(difluoromethyl)-2-fluorophenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate (3.1 mg, 4.44 μmol, 7.38% yield) was prepared in asimilar manner as the procedure described in Example 56 using6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)pyrimidin-4-ol (16.51 mg,0.060 mmol). ¹H NMR (400 MHz, CD₃OD) δ 8.78 (d, J=5.3 Hz, 1H), 7.80-7.74(m, 2H), 7.60 (d, J=8.6 Hz, 1H), 7.56 (dd, J=5.3, 1.5 Hz, 1H), 7.53 (s,1H), 7.16-6.84 (m, 1H), 6.67 (s, 1H), 6.08 (dd, J=12.8, 4.2 Hz, 1H),4.08 (s, 3H), 2.75 (td, J=6.8, 3.2 Hz, 1H), 2.40 (tt, J=12.7, 4.6 Hz,1H), 2.19-2.05 (m, 2H), 1.71-1.60 (m, 1H), 1.53 (ddd, J=15.0, 9.9, 5.5Hz, 1H), 1.05 (d, J=7.0 Hz, 3H), 0.76 (br. s., 1H); MS(ESI) m/z: 557.1(M+H)⁺. Analytical HPLC (Method A): RT=7.516 min, purity=96.0%; FactorXIa Ki=2.5 nM, Plasma Kallikrein Ki=45 nM.

Example 62 Preparation of(9R,13S)-13-{4-[3-chloro-6-(1,1-difluoroethyl)-2-fluorophenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate

62A. Preparation of 1-chloro-4-(1,1-difluoroethyl)-2-fluorobenzene

To a sealed tube was added 1-(4-chloro-3-fluorophenyl)ethanone (1 g,5.79 mmol), CH₂Cl₂ (10 mL) and DAST (2.297 mL, 17.38 mmol). The reactionwas sealed and stirred at 45° C. for 8 h. The reaction was carefullyquenched with cold sat NaHCO₃ over 30 min until the pH was greater than7. The organic layer was separated, washed with water, dried over MgSO₄,filtered and concentrated. The reside was purified using ISCO system(0-10% EtOAC/Hex gradient) to give1-chloro-4-(1,1-difluoroethyl)-2-fluorobenzene (300 mg, 1.54 mmol, 26.6%yield) as a light brown liquid. ¹H NMR (400 MHz, CDCl₃) δ 7.49-7.42 (m,1H), 7.32-7.27 (m, 1H), 7.25-7.20 (m, 1H), 1.90 (t, J=18.2 Hz, 3H).

62B. Preparation of2-(3-chloro-6-(1,1-difluoroethyl)-2-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

To a dry RBF was added 1-chloro-4-(1,1-difluoroethyl)-2-fluorobenzene(230 mg, 1.182 mmol) and THF (3 mL). The reaction was cooled to −78° C.and 2 M LDA solution (0.71 mL, 1.418 mmol) was added dropwise. Thereaction turned to red after the addition. The reaction was stirred at−78° C. for 5 min and then2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (440 mg, 2.364mmol) was added in one portion. The reaction was stirred at −78° C. foradditional 20 min. The color changed to pale yellow. The reaction waspartitioned between EtOAc (30 mL) and water (20 mL). The organic layerwas separated, washed with water (20 mL) and brine (20 mL), dried overMgSO₄, filtered and concentrated. The residue was purified using ISCOsystem (0-30% EtOAc/Hex gradient) to give2-(3-chloro-6-(1,1-difluoroethyl)-2-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(330 mg, 1.030 mmol, 87% yield) as a clear oil. ¹H NMR (400 MHz, CDCl₃)δ 7.43 (t, J=7.9 Hz, 1H), 7.18 (d, J=8.4 Hz, 1H), 1.93 (t, J=18.3 Hz,3H), 1.38 (s, 12H).

62C. Preparation of4-(3-chloro-6-(1,1-difluoroethyl)-2-fluorophenyl)-6-methoxypyrimidine

To a microwave vial was added2-(3-chloro-6-(1,1-difluoroethyl)-2-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(325 mg, 1.014 mmol), 4-chloro-6-methoxypyrimidine (147 mg, 1.014 mmol),toluene (4 mL), EtOH (2 mL) and 2 M Na₂CO₃ (1.52 mL, 3.04 mmol). Thereaction was purged with Ar and Pd(PPh₃)₄ (116.7 mg, 0.101 mmol) wasadded. The reaction was sealed and stirred in microwave at 120° C. for 1h. The reaction was partitioned between EtOAc (20 mL) and water (20 mL).The organic layer was separated, washed with water (10 mL) and brine (15mL), dried over MgSO₄, filtered and concentrated. The residue waspurified using ISCO system (0-30% EtOAc/Hex gradient) to give4-(3-chloro-6-(1,1-difluoroethyl)-2-fluorophenyl)-6-methoxypyrimidine(40 mg, 0.132 mmol, 13.03% yield) as a white solid. ¹H NMR (400 MHz,CDCl₃) δ 8.84 (d, J=1.1 Hz, 1H), 7.52 (d, J=7.3 Hz, 1H), 7.36 (dd,J=8.6, 1.3 Hz, 1H), 6.81 (s, 1H), 4.05 (s, 3H), 1.91 (t, J=18.6 Hz, 3H);MS(ESI) m/z: 303.0, 305.0 (M+H)⁺.

62D. Preparation of6-(3-chloro-6-(1,1-difluoroethyl)-2-fluorophenyl)pyrimidin-4-ol

To a RBF was added4-(3-chloro-6-(1,1-difluoroethyl)-2-fluorophenyl)-6-methoxypyrimidine(35 mg, 0.116 mmol), AcOH (0.5 mL) and HBr (0.654 mL, 5.78 mmol). Thereaction was stirred at 85° C. for 45 min. Then toluene (25 mL) wasadded and the reaction was concentrated. The residue was partitionedbetween EtOAc (25 mL) and sat NaHCO₃ (25 mL). The organic layer wasseparated, washed with water (15 mL) and brine (15 mL), dried overMgSO₄, filtered and concentrated. The residue was purified using ISCOsystem (0-100% EtOAc/Hex gradient) to give6-(3-chloro-6-(1,1-difluoroethyl)-2-fluorophenyl)pyrimidin-4-ol (28 mg,0.097 mmol, 84% yield) as a white solid. MS(ESI) m/z: 289, 291.0 (M+H)⁺.

62E. Preparation of(9R,13S)-13-{4-[3-chloro-6-(1,1-difluoroethyl)-2-fluorophenyl]-6-oxo-1,6-ihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate

(9R,13S)-13-{4-[3-Chloro-6-(1,1-difluoroethyl)-2-fluorophenyl]-6-oxo-1,6-ihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate (30 mg, 0.042 mmol, 69.9% yield) was prepared in asimilar manner as the procedure described in Example 56 by replacing6-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}pyrimidin-4-olwith 6-(3-chloro-6-(1,1-difluoroethyl)-2-fluorophenyl)pyrimidin-4-ol(22.2 mg, 0.06 mmol). ¹H NMR (400 MHz, CD₃OD) δ 8.99 (br. s., 1H), 8.74(d, J=4.2 Hz, 1H), 7.78 (s, 1H), 7.65 (t, J=7.8 Hz, 1H), 7.58 (d, J=3.7Hz, 1H), 7.50-7.39 (m, 2H), 6.53 (s, 1H), 6.01 (d, J=9.9 Hz, 1H), 4.02(s, 3H), 2.67 (br. s., 1H), 2.43-2.31 (m, 1H), 2.06 (br. s., 2H), 1.89(t, J=18.6 Hz, 3H), 1.66-1.53 (m, 1H), 1.45 (br. s., 1H), 0.98 (d, J=6.8Hz, 3H), 0.73 (br. s., 1H); MS(ESI) m/z: 636.2 (M+H)⁺. Analytical HPLC(Method A): RT=11.078 min, purity=96.0%; Factor XIa Ki=16 nM, PlasmaKallikrein Ki=240 nM.

Example 63 Preparation of(9R,13S)-13-{4-[3-chloro-2-fluoro-6-(1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-16-fluoro-3,9-dimethyl-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

To 6-[3-chloro-2-fluoro-6-(1H-1,2,3-triazol-1-yl)phenyl]pyrimidin-4-ol(0.018 g, 0.060 mmol), prepared as described in Intermediate 7, wasadded HATU (0.030 g, 0.078 mmol) and a solution of DBU (0.014 mL, 0.090mmol) in CH₃CN (0.5 ml). After 30 min,(9R,13S)-13-amino-16-fluoro-3,9-dimethyl-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1-(18),2(6),4,14,16-pentaen-8-one(0.019 g, 0.060 mmol), prepared as described in Intermediate 29, wasadded. After 18 h, the reaction was diluted with DMF, filtered andconcentrated. The residue was purified by reverse phase HPLC usingPHENOMENEX® Luna 5U 30×100 mm (10:90 ACN/H₂O to 90:10 AcN/H₂O, 0.1% TFA)(20% B start 10 min gradient). The desired fractions were concentratedand freeze-dried to afford(9R,13S)-13-{4-[3-chloro-2-fluoro-6-(1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-16-fluoro-3,9-dimethyl-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1-(18),2(6),4,14,16-pentaen-8-one(4.5 mg, 12%) as a white solid. MS(ESI) m/z: 591.3 (M+H)⁺. ¹H NMR (400MHz, CD₃OD) δ 8.25 (s, 1H), 8.20 (d, J=1.1 Hz, 1H), 7.91-7.84 (m, 1H),7.84-7.77 (m, 2H), 7.60-7.49 (m, 3H), 7.38 (d, J=8.6 Hz, 1H), 7.12 (d,J=9.5 Hz, 1H), 6.59 (s, 1H), 5.79 (dd, J=12.9, 3.2 Hz, 1H), 4.08-4.00(m, 3H), 2.52 (td, J=6.8, 3.4 Hz, 1H), 2.41-2.29 (m, 1H), 2.15-2.04 (m,1H), 1.90 (d, J=4.8 Hz, 1H), 1.65-1.45 (m, 2H), 1.29-1.19 (m, 1H), 1.14(d, J=6.8 Hz, 3H). Analytical HPLC (Method A) RT=7.41 min, purity=95%;Factor XIa Ki=0.25 nM, Plasma Kallikrein Ki=34 nM.

Example 64 Preparation of(9R,13S)-13-[4-(3-chloro-2,6-difluorophenyl)-6-oxo-1,6-dihydropyrimidin-1-yl]-16-fluoro-3,9-dimethyl-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

To a solution of 6-(3-chloro-2,6-difluorophenyl)pyrimidin-4-olhydrobromide (0.017 g, 0.053 mmol), prepared as described inIntermediate 4, in CH₃CN (1 ml), was added HATU (0.026 g, 0.068 mmol)and DBU (0.028 mL, 0.184 mmol). After 1 h,(9R,13S)-13-amino-16-fluoro-3,9-dimethyl-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one,(0.019 g, 0.053 mmol), prepared as described in Intermediate 29, wasadded. After 18 h, the reaction was diluted with DMF, filtered andconcentrated. The residue was purified by reverse phase HPLC, thenpreparative LCMS to give(9R,13S)-13-[4-(3-chloro-2,6-difluorophenyl)-6-oxo-1,6-dihydropyrimidin-1-yl]-16-fluoro-3,9-dimethyl-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(3.4 mg, 11.9%). MS(ESI) m/z: 542.1 (M+H)⁺. ¹H NMR ((500 MHz, DMSO-d₆) δ9.23 (s, 1H), 8.69 (br. s., 1H), 7.84-7.73 (m, 1H), 7.61-7.50 (m, 2H),7.45 (s, 1H), 7.38-7.32 (m, 1H), 7.29-7.19 (m, 1H), 6.74 (s, 1H), 5.66(d, J=12.5 Hz, 1H), 3.98 (s, 3H), 2.42 (br. s., 1H), 2.10-1.97 (m, 1H),1.88 (br. s., 1H), 1.45 (d, J=7.3 Hz, 1H), 1.21 (br. s., 1H), 1.11 (br.s., 1H), 0.97 (d, J=6.4 Hz, 3H). Analytical HPLC (Method C) RT=1.50min., purity=99%; Factor XIa Ki=26 nM, Plasma Kallikrein Ki=450 nM.

Example 65 Preparation of(9R,13S)-13-{4-[3-chloro-2-fluoro-6-(1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

To 6-[3-chloro-2-fluoro-6-(1H-1,2,3-triazol-1-yl)phenyl]pyrimidin-4-ol(13.07 mg, 0.045 mmol), prepared as described in Intermediate 7, wasadded HATU (22.14 mg, 0.058 mmol) and a solution of DBU (0.017 mL, 0.112mmol) in ACN (0.5 ml). After 30 min,(9R,13S)-13-amino-3,9-dimethyl-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one,hydrochloride (15 mg, 0.045 mmol), prepared as described in Intermediate31, was added and the reaction was stirred for 18 h. The reaction wasthen diluted with DMF, filtered and concentrated. The residue waspurified by reverse phase HPLC, then, preparative LCMS to give(9R,13S)-13-{4-[3-chloro-2-fluoro-6-(1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(3.2 mg, 12%). MS(ESI) m/z: 573.3 (M+H)⁺. ¹H NMR (500 MHz, DMSO-d₆) δ9.15 (s, 1H), 8.43-8.32 (m, 2H), 8.00-7.93 (m, 2H), 7.84 (s, 1H),7.68-7.59 (m, 2H), 7.59-7.50 (m, 2H), 7.41 (s, 1H), 7.28-6.99 (m, 2H),6.56 (s, 1H), 5.60 (d, J=11.3 Hz, 1H), 4.03-3.90 (m, 3H), 2.32 (br. s.,1H), 1.94-1.79 (m, 2H), 1.41 (d, J=5.2 Hz, 1H), 1.14 (br. s., 2H), 0.96(d, J=6.4 Hz, 3H). Analytical HPLC (Method C) RT=1.41 min., purity=98%;Factor XIa Ki=0.23 nM, Plasma Kallikrein Ki=22 nM.

Example 66 Preparation of(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

To a 1-dram vial containing a white suspension of6-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]pyrimidin-4-ol(0.026 g, 0.084 mmol), prepared as described in Intermediate 9, in CH₃CN(0.5 ml) was added HATU (0.041 g, 0.109 mmol) and DBU (0.019 mL, 0.126mmol). After 30 min,(9R,13S)-13-amino-3,9-dimethyl-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(0.025 g, 0.084 mmol), prepared as described in Intermediate 31, whichhad been free-based through a basic cartridge in DCM/MeOH and dried, inCH₃CN/DMF (0.5 ml) was added. After 18 h, the reaction was diluted withDMF, filtered and purified by reverse phase HPLC using PHENOMENEX® Luna5U 30×100 mm (10:90 MeOH/H₂O to 90:10 MeOH/H₂O, 0.1% TFA) (20% B start10 min gradient) to afford(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(13.9 mg, 28% yield) as a white solid. MS(ESI) m/z: 589.2 (M+H)⁺. ¹H NMR(400 MHz, CD₃OD) δ 8.37-8.33 (m, 1H), 8.19 (s, 1H), 7.88 (d, J=2.4 Hz,1H), 7.80-7.72 (m, 2H), 7.67-7.55 (m, 3H), 7.52 (s, 1H), 7.34 (d, J=7.3Hz, 1H), 6.43 (d, J=0.7 Hz, 1H), 5.84 (dd, J=13.1, 3.2 Hz, 1H), 4.04 (s,3H), 2.55-2.46 (m, 1H), 2.41-2.30 (m, 1H), 2.17-2.05 (m, 1H), 1.92-1.84(m, 1H), 1.66-1.53 (m, 2H), 1.22 (br. s., 1H), 1.16 (d, J=6.8 Hz, 3H).Analytical HPLC (Method A) RT=8.25 min., purity=95%; Factor XIa Ki=0.1nM, Plasma Kallikrein Ki=8 nM.

Example 67 Preparation of(9R)-13-{4-[3-chloro-2-fluoro-6-(1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

Purification of Example 65 by reverse phase HPLC, then, preparative LCMSalso gave(9R)-13-{4-[3-chloro-2-fluoro-6-(1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-oneas the first eluting diastereomer (1.4 mg, 5.4%). MS(ESI) m/z: 573.3(M+H)⁺. ¹H NMR (500 MHz, DMSO-d₆)¹H NMR (500 MHz, DMSO-d₆) δ 9.08 (s,1H), 8.71 (s, 1H), 8.39 (s, 1H), 8.04-7.94 (m, 1H), 7.86 (s, 1H),7.70-7.58 (m, 2H), 7.58-7.48 (m, 2H), 7.42 (s, 1H), 7.25-7.03 (m, 2H),6.61 (s, 1H), 5.60 (d, J=13.1 Hz, 1H), 3.98 (s, 2H), 2.41-2.30 (m, 2H),1.82 (br. s., 1H), 1.68 (d, J=10.1 Hz, 1H), 1.37 (d, J=11.0 Hz, 1H),1.11 (br. s., 2H), 1.07 (d, J=6.4 Hz, 3H). Analytical HPLC (Method C)RT=1.39 min., purity=100%; Factor XIa Ki=5 nM, Plasma Kallikrein Ki=256nM.

Example 68 Preparation of(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(²H₃)methyl-9-methyl-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

To a solution of6-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]pyrimidin-4-ol(0.031 g, 0.100 mmol), prepared as described in Intermediate 9, in CH₃CN(0.8 ml) was added HATU (0.049 g, 0.129 mmol) and DBU (0.023 mL, 0.149mmol) After 30 min,(9R,13S)-13-amino-3-(²H₃)methyl-9-methyl-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one0.03 g, 0.100 mmol), prepared as described in Intermediate 36, was added(rinsed in with 0.2 ml DMF). After 18 h, the reaction was diluted withDMF, filtered and concentrated. The residue was purified by reversephase HPLC using PHENOMENEX® Luna 5U 30×100 mm (10:90 MeOH/H₂O to 90:10MeOH/H₂O, 0.1% TFA) (25% B start, 14 min gradient). The desiredfractions were concentrated and freeze-dried to afford(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(²H₃)methyl-9-methyl-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(19.6 mg, 33% yield) as a tan solid. MS(ESI) m/z: 592.4 (M+H)⁺. ¹H NMR(400 MHz, CD₃OD) δ 8.33 (s, 1H), 8.18 (s, 1H), 7.87 (d, J=2.2 Hz, 1H),7.80-7.71 (m, 2H), 7.68-7.55 (m, 3H), 7.54-7.50 (m, 1H), 7.33 (d, J=7.5Hz, 1H), 6.42 (s, 1H), 5.83 (dd, J=12.8, 3.1 Hz, 1H), 2.56-2.45 (m, 1H),2.38-2.29 (m, 1H), 2.18-2.06 (m, 1H), 1.94-1.82 (m, 1H), 1.67-1.52 (m,2H), 1.22 (br. s., 1H), 1.15 (d, J=6.8 Hz, 3H). Analytical HPLC (MethodA) RT=8.44 min, 95% purity; Factor XIa Ki=0.1 nM, Plasma Kallikrein Ki=6nM.

Example 69 Preparation of(10R,14S)-14-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-10-methyl-3,8-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-9-onetrifluoroacetate

To a solution of6-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]pyrimidin-4-ol(4.42 mg, 0.014 mmol), prepared as described in Intermediate 10, inCH₃CN (0.2 ml) was added HATU (6.69 mg, 0.018 mmol) and DBU (3.06 μl,0.020 mmol). After 30 min,(10R,14S)-14-amino-10-methyl-3,8-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-9-one(0.004 g, 0.014 mmol), prepared as described in Intermediate 38, wasadded with DMF (0.2 ml). After 18 h, the reaction was diluted with DMF,filtered and concentrated. The residue was purified by reverse phaseHPLC using PHENOMENEX® Luna 5U 30×100 mm (10:90 ACN/H₂O to 90:10ACN/H₂O, 0.1% TFA) (20% B start, 14 min gradient) to afford(10R,14S)-14-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-10-methyl-3,8-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-9-onetrifluoroacetate (2 mg, 20% yield) as a white solid. MS(ESI) m/z: 604.4(M+H)⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.69-8.65 (m, 1H), 8.38-8.30 (m, 2H),8.00-7.91 (m, 2H), 7.91-7.84 (m, 1H), 7.74 (d, J=7.9 Hz, 1H), 7.69-7.63(m, 2H), 7.55 (dd, J=8.6, 1.5 Hz, 1H), 7.36 (d, J=7.7 Hz, 1H), 6.64 (s,1H), 5.83 (dd, J=12.9, 3.4 Hz, 1H), 2.55 (t, J=6.7 Hz, 1H), 2.40-2.29(m, 1H), 2.21-2.10 (m, 1H), 1.89 (br. s., 1H), 1.65-1.51 (m, 2H), 1.33(d, J=9.7 Hz, 1H), 1.15 (d, J=6.8 Hz, 3H). Analytical HPLC (Method A)RT=6.32 min. Purity=100%; Factor XIa Ki=1.1 nM, Plasma Kallikrein Ki=54nM.

Example 70 Preparation of1-(4-chloro-2-{1-[(9R,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}-3-fluorophenyl)-1H-1,2,3-triazole-4-carbonitrile

To a solution of1-[4-chloro-3-fluoro-2-(6-hydroxypyrimidin-4-yl)phenyl]-1H-1,2,3-triazole-4-carbonitrile(13.0 mg, 0.041 mmol), prepared as described in Intermediate 12, inCH₃CN (0.4 ml) was added HATU (0.020 g, 0.053 mmol) and DBU (9.28 μl,0.062 mmol). After 0.5 h,(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(14.0 mg, 0.041 mmol), prepared as described in Intermediate 35, wasadded with DMF (0.2 ml). Additional CH₃CN (0.2 ml) and DMF (0.2 ml) wereadded to rinse the vials and dissolve reagents. After 18 h, the reactionwas diluted with DMF, filtered and concentrated. The residue waspurified by reverse phase HPLC using PHENOMENEX® Luna 5U 30×100 mm(10:90 ACN/H₂O to 90:10 ACN/H₂O, 0.1% TFA) (20% B start, 14 mingradient) to afford1-(4-chloro-2-{1-[(9R,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}-3-fluorophenyl)-1H-1,2,3-triazole-4-carbonitrile(6 mg, 24.7% yield) as a white solid. MS(ESI) m/z: 643.3 (M+H)⁺. ¹H NMR(400 MHz, CD₃OD) δ 8.96 (br. s., 1H), 8.22 (br. s., 1H), 7.90 (d, J=6.8Hz, 1H), 7.79 (br. s., 2H), 7.71-7.55 (m, 4H), 7.39 (br. s., 1H), 6.71(br. s., 1H), 5.84 (d, J=9.9 Hz, 1H), 2.52 (br. s., 1H), 2.37 (br. s.,1H), 2.19-2.01 (m, 1H), 2.01-1.87 (m, 1H), 1.59 (br. s., 2H), 1.23 (br.s., 1H), 1.17 (br. s., 3H). Analytical HPLC (Method A) rt=8.83 min,purity=99%; Factor XIa Ki=0.1 nM, Plasma Kallikrein Ki=4 nM.

Example 71 Preparation of(9R,13S)-13-(4-{5-chloro-2-[4-(difluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

To a solution of6-{5-chloro-2-[4-(difluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}pyrimidin-4-ol(0.014 g, 0.043 mmol), prepared as described in Intermediate 16, inCH₃CN (0.4 ml) was added HATU (0.021 g, 0.056 mmol) and DBU (9.78 μl,0.065 mmol). After 30 min,(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(0.14 g, 0.043 mmol), prepared as described in Intermediate 35, wasadded with DMF (0.2 ml). Additional CH₃CN (0.2 ml) and DMF (0.2 ml) wereadded to rinse vials and dissolve reagents. After 18 h, the reaction wasdiluted with DMF, filtered and concentrated. The residue was purified byreverse phase HPLC using PHENOMENEX® Luna 5U 30×100 mm (10:90 ACN/H₂O to90:10 ACN/H₂O, 0.1% TFA) (20% B start, 14 min gradient) to afford(9R,13S)-13-(4-{5-chloro-2-[4-(difluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(9.9 mg, 35.7%) as a white solid. MS(ESI) m/z: 641.5 (M+H)⁺. ¹H NMR (400MHz, CD₃OD) δ 8.53 (t, J=1.3 Hz, 1H), 8.19 (s, 1H), 7.88 (d, J=2.4 Hz,1H), 7.82-7.72 (m, 3H), 7.68 (s, 1H), 7.65-7.56 (m, 3H), 7.38 (d, J=7.5Hz, 1H), 7.20-6.81 (m, 1H), 6.42 (d, J=0.7 Hz, 1H), 5.82 (dd, J=12.8,3.3 Hz, 1H), 2.50 (ddd, J=10.2, 6.9, 3.4 Hz, 1H), 2.35 (d, J=12.5 Hz,1H), 2.19-2.08 (m, 1H), 1.97-1.86 (m, 1H), 1.65-1.52 (m, 2H), 1.27-1.20(m, 1H), 1.16 (d, J=6.8 Hz, 3H). Analytical HPLC (Method A) RT=8.79 min,purity=100%; Factor XIa Ki=0.17 nM, Plasma Kallikrein Ki=46 nM.

Example 72 Preparation of(9R,13S)-13-(4-{5-chloro-2-[4-(difluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(²H₃)methyl-9-methyl-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

To a solution of6-{5-chloro-2-[4-(difluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}pyrimidin-4-ol(0.014 g, 0.043 mmol), prepared as described in Intermediate 16, inCH₃CN (0.4 ml) was added HATU (0.021 g, 0.056 mmol) and DBU (9.78 μl,0.065 mmol). After 30 min,(9R,13S)-13-amino-3-(²H₃)methyl-9-methyl-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(0.13 g, 0.043 mmol) prepared as described in Intermediate 36, was addedwith DMF (0.2 ml). Additional CH₃CN (0.2 ml) and DMF (0.4 ml) were addedto dissolve reagents. After 18 h, the reaction was diluted with DMF,filtered and concentrated. The residue was purified by reverse phaseHPLC using PHENOMENEX® Luna 5U 30×100 mm (10:90 ACN/H₂O to 90:10ACN/H₂O, 0.1% TFA) (20% B start, 14 min gradient) to afford(9R,13S)-13-(4-{5-chloro-2-[4-(difluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(²H₃)methyl-9-methyl-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(10.5 mg, 39%) as a white solid. MS(ESI) m/z: 608.3 (M+H)⁺. ¹H NMR (400MHz, CD₃OD) δ 8.52 (t, J=1.3 Hz, 1H), 8.14 (s, 1H), 7.93-7.87 (m, 1H),7.75 (dd, J=8.5, 2.3 Hz, 2H), 7.72-7.66 (m, 1H), 7.64-7.54 (m, 2H),7.54-7.50 (m, 1H), 7.35-7.30 (m, 1H), 7.14-6.83 (m, 1H), 6.43 (d, J=0.7Hz, 1H), 5.83 (dd, J=13.0, 3.3 Hz, 1H), 2.49 (dt, J=6.9, 3.4 Hz, 1H),2.40-2.27 (m, 1H), 2.09 (d, J=12.3 Hz, 1H), 1.95-1.84 (m, 1H), 1.67-1.52(m, 2H), 1.21 (d, J=6.8 Hz, 1H), 1.16 (d, J=6.8 Hz, 3H) Analytical HPLC(Method A) RT=7.94 min, purity=99%; Factor XIa Ki=0.15 nM, PlasmaKallikrein Ki=21 nM.

Example 73 Preparation of1-(4-chloro-3-fluoro-2-{1-[(9R,13S)-3-(²H₃)methyl-9-methyl-8-oxo-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)-1H-1,2,3-triazole-4-carbonitrile

To a solution of1-[4-chloro-3-fluoro-2-(6-hydroxypyrimidin-4-yl)phenyl]-1H-1,2,3-triazole-4-carbonitrile(0.010 g, 0.032 mmol), prepared as described in Intermediate 12, inCH₃CN (0.4 ml) was added HATU (0.016 g, 0.041 mmol) and DBU (7.14 μl,0.047 mmol). After 30 min,(9R,13S)-13-amino-3-(²H₃)methyl-9-methyl-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(0.095 g, 0.032 mmol), prepared as described in Intermediate 36, wasadded with DMF (0.2 ml). Additional CH₃CN (0.2 ml) and DMF (0.2 ml) wereadded to dissolve reagents. After 18 h, the reaction was diluted withDMF, filtered and concentrated. The residue was purified by reversephase HPLC using PHENOMENEX® Luna 5U 30×100 mm (10:90 ACN/H₂O to 90:10ACN/H₂O, 0.1% TFA) (20% B start, 14 min gradient) to afford1-(4-chloro-3-fluoro-2-{1-[(9R,13S)-3-(²H₃)methyl-9-methyl-8-oxo-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)-1H-1,2,3-triazole-4-carbonitrile(4.7 mg, 24%) as a white solid. MS(ESI) m/z: 601.3 (M+H)⁺. ¹H NMR (400MHz, CD₃OD) δ 8.94 (s, 1H), 8.16 (s, 1H), 7.90 (dd, J=8.7, 7.6 Hz, 1H),7.77 (s, 1H), 7.70-7.56 (m, 3H), 7.56-7.49 (m, 1H), 7.32 (d, J=7.7 Hz,1H), 6.79-6.66 (m, 1H), 5.85 (dd, J=12.7, 3.2 Hz, 1H), 2.50 (ddd,J=10.2, 6.7, 3.5 Hz, 1H), 2.39-2.30 (m, 1H), 2.20-2.06 (m, 1H), 1.90(dd, J=9.6, 4.5 Hz, 1H), 1.69-1.53 (m, 2H), 1.28-1.22 (m, 1H), 1.16 (d,J=6.8 Hz, 3H). Analytical HPLC (Method A) RT=7.99 min, purity=97%;Factor XIa Ki=0.15 nM, Plasma Kallikrein Ki=9 nM.

Example 74 Preparation of1-(4-chloro-2-{1-[(9R,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)-1H-1,2,3-triazole-4-carbonitrile

To a solution of1-[4-chloro-2-(6-hydroxypyrimidin-4-yl)phenyl]-1H-1,2,3-triazole-4-carbonitrile(0.016 g, 0.054 mmol), prepared as described in Intermediate 18, inCH₃CN (0.4 ml) was added HATU (0.026 g, 0.070 mmol) and DBU (0.012 mL,0.080 mmol). After 30 min,(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(0.018 g, 0.054 mmol), prepared as described in Intermediate 35, wasadded with DMF (0.5 ml). After 18 h, the reaction was diluted with DMF,filtered and concentrated. The residue was purified by reverse phaseHPLC using PHENOMENEX® Luna 5U 30×100 mm (10:90 ACN/H₂O to 90:10ACN/H₂O, 0.1% TFA) (20% B start, 14 min gradient) to afford1-(4-chloro-2-{1-[(9R,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)-1H-1,2,3-triazole-4-carbonitrile(11.7 mg, 34%) as a white solid. MS(ESI) m/z: 616.2 (M+H)⁺. ¹H NMR (400MHz, CD₃OD) δ 8.96 (s, 1H), 8.19 (s, 1H), 7.94-7.89 (m, 1H), 7.84-7.74(m, 4H), 7.72-7.66 (m, 1H), 7.66-7.61 (m, 1H), 7.60-7.55 (m, 1H), 7.40(d, J=7.5 Hz, 1H), 6.52 (s, 1H), 5.83 (dd, J=12.9, 3.4 Hz, 1H), 2.50(td, J=6.6, 3.7 Hz, 1H), 2.42-2.31 (m, 1H), 2.17-2.07 (m, 1H), 1.90 (dd,J=10.0, 4.7 Hz, 1H), 1.63-1.53 (m, 2H), 1.28-1.20 (m, 1H), 1.16 (d,J=6.8 Hz, 3H). Analytical HPLC (Method A) RT=8.82, purity=97%; FactorXIa Ki=0.1 nM, Plasma Kallikrein Ki=10 nM.

Example 75 Preparation of(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

To a solution of6-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}pyrimidin-4-ol(0.029 g, 0.084 mmol), prepared as described in Intermediate 15, inCH₃CN (0.8 ml) was added HATU (0.041 g, 0.109 mmol) and DBU (0.019 mL,0.126 mmol). After 30 min,(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(0.028 g, 0.084 mmol), prepared as described in Example 35, was addedwith DMF (0.4 ml). The reaction was stirred 4 h then was diluted withDMF, filtered and concentrated. The residue was purified by reversephase HPLC using PHENOMENEX® Luna 5U 30×100 mm (10:90 ACN/H₂O to 90:10ACN/H₂O, 0.1% TFA) (20% B start, 14 min gradient) to afford(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(18.8 mg, 34%) as a white solid. MS(ESI) m/z: 659.03 (M+H)⁺. ¹H NMR (400MHz, CD₃OD) δ 8.81 (d, J=0.7 Hz, 1H), 8.18 (s, 1H), 7.89 (d, J=2.4 Hz,1H), 7.82-7.74 (m, 3H), 7.70 (s, 1H), 7.64-7.56 (m, 3H), 7.42-7.36 (m,1H), 6.49 (d, J=0.7 Hz, 1H), 5.83 (dd, J=12.9, 3.2 Hz, 1H), 2.50 (ddd,J=10.2, 6.8, 3.4 Hz, 1H), 2.35 (d, J=12.3 Hz, 1H), 2.15-2.06 (m, 1H),1.94-1.85 (m, 1H), 1.65-1.51 (m, 2H), 1.31-1.20 (m, 1H), 1.16 (d, J=6.8Hz, 3H). Analytical HPLC (Method A) RT=9.40 min, purity=100%; Factor XIaKi=0.1 nM, Plasma Kallikrein Ki=15 nM.

Example 76 Preparation of(10R,14S)-14-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-10-methyl-3,8-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-9-one

To a solution of6-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}pyrimidin-4-ol(0.035 g, 0.102 mmol), prepared as described in Intermediate 15, inCH₃CN (0.4 ml) was added HATU (0.050 g, 0.132 mmol) and DBU (0.023 mL,0.152 mmol). After 30 min,(10R,14S)-14-amino-10-methyl-3,8-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-9-one(0.030 g, 0.102 mmol), prepared as described in Intermediate 38, wasadded with DMF (0.6 ml). After 18 h, the reaction was diluted with DMF,filtered and concentrated. The residue was purified by preparative LCMSusing (5:95 ACN/H₂O to 95:5 ACN/H₂O, 0.1% TFA) to afford(10R,14S)-14-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-10-methyl-3,8-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-9-one(8.6 mg, 11.1%). MS(ESI) m/z: 620.08 (M+H)⁺. ¹H NMR (400 MHz, CD₃OD) δ8.81-8.72 (m, 1H), 8.59 (d, J=4.3 Hz, 1H), 8.16 (s, 1H), 7.88-7.83 (m,2H), 7.78-7.65 (m, 4H), 7.58-7.53 (m, 1H), 7.53-7.48 (m, 1H), 7.28 (d,J=7.6 Hz, 1H), 6.43 (s, 1H), 5.88-5.72 (m, 1H), 2.49 (br. s., 1H), 2.27(d, J=10.4 Hz, 1H), 2.10 (d, J=10.1 Hz, 1H), 1.85 (d, J=8.9 Hz, 1H),1.55 (d, J=9.8 Hz, 2H), 1.28 (br. s., 1H), 1.13 (d, J=6.7 Hz, 3H).Analytical HPLC (Method C) RT=1.55 min, purity=97%; Factor XIa Ki=1.7nM, Plasma Kallikrein Ki=130 nM.

Example 77 Preparation of(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,17-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

To a solution of6-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]pyrimidin-4-ol(0.019 g, 0.060 mmol), prepared as described in Intermediate 9, in CH₃CN(0.4 ml) was added HATU (0.030 g, 0.078 mmol) and DBU (0.014 mL, 0.090mmol). After 30 min,(9R,13S)-13-amino-3,9-dimethyl-3,4,7,17-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one,prepared as described in Intermediate 42, was added with DMF (0.2 ml).After 18 h, the reaction was diluted with DMF, filtered andconcentrated. The residue was purified by reverse phase HPLC usingPHENOMENEX® Luna 5U 30×100 mm (10:90 ACN/H₂O to 90:10 ACN/H₂O, 0.1% TFA)(20% B start, 14 min gradient) to afford(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,17-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(11.9 mg, 27%) as an off-white solid. MS(ESI) m/z: 590.3 (M+H)⁺. ¹H NMR(400 MHz, CD₃OD) δ d 8.78-8.70 (m, 1H), 8.41-8.33 (m, 2H), 7.92-7.85 (m,2H), 7.80-7.73 (m, 1H), 7.71-7.65 (m, 1H), 7.51 (s, 1H), 7.21 (dd,J=5.3, 1.8 Hz, 1H), 6.50-6.42 (m, 1H), 5.77 (dd, J=12.5, 3.1 Hz, 1H),4.23-4.16 (m, 3H), 2.69-2.58 (m, 1H), 2.41 (dd, J=7.5, 4.2 Hz, 1H),2.22-2.09 (m, 1H), 2.07-1.96 (m, 1H), 1.74-1.60 (m, 1H), 1.38 (d, J=7.7Hz, 2H), 1.15 (d, J=7.0 Hz, 3H). Analytical HPLC (Method A) RT=7.38 min,purity=96%; Factor XIa Ki=0.2 nM, Plasma Kallikrein Ki=23 nM.

Example 78 Preparation of(9R,13S)-13-{4-[2-(4-bromo-1H-1,2,3-triazol-1-yl)-5-chlorophenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(²H₃)methyl-9-methyl-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

To 6-[2-(4-bromo-1H-1,2,3-triazol-1-yl)-5-chlorophenyl]pyrimidin-4-ol(0.05 g, 0.142 mmol) and HATU (0.070 g, 0.184 mmol) in a small vial wasadded DBU (0.032 mL, 0.213 mmol) in CH₃CN (0.8 ml). After 30 min,(9R,13S)-13-amino-3-(²H₃)methyl-9-methyl-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(0.043 g, 0.142 mmol), prepared as described in Intermediate 36, wasadded and the vial was rinsed with DMF (0.2 ml). After 18 h, thereaction was diluted with DMF, filtered and purified by reverse phaseHPLC using PHENOMENEX® Luna 5U 30×100 mm (10:90 MeOH/H₂O to 90:10MeOH/H₂O, 0.1% TFA) (20% B start, 14 min gradient) to afford(9R,13S)-13-{4-[2-(4-bromo-1H-1,2,3-triazol-1-yl)-5-chlorophenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(²H₃)methyl-9-methyl-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(30 mg, 33%) as a white solid. This compound was used in subsequentreaction and a small amount (4 mg, white solid after freeze-drying) wasisolated by preparative LCMS using (5:95 AcN/H₂O to 95:5 AcN/H₂O, 10 mMNH₄OAc). MS(ESI) m/z: 638.4 (M+H)⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.25 (s,1H), 8.06 (s, 1H), 7.75 (d, J=2.4 Hz, 1H), 7.68-7.59 (m, 2H), 7.56-7.43(m, 3H), 7.40-7.36 (m, 1H), 7.21 (d, J=7.5 Hz, 1H), 6.30 (s, 1H), 5.71(dd, J=12.7, 3.2 Hz, 1H), 2.43-2.32 (m, 1H), 2.28-2.18 (m, 1H), 1.98 (d,J=12.3 Hz, 1H), 1.84-1.73 (m, 1H), 1.56-1.41 (m, 2H), 1.10 (br. s., 1H),1.03 (d, J=6.8 Hz, 3H). Analytical HPLC (Method C) RT=1.60 min,purity=96%; Factor XIa Ki=0.1 nM, Plasma Kallikrein Ki=7 nM.

Example 79 Preparation of(9R,13S)-13-(4-{5-chloro-2-[4-(pyrimidin-2-yl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(²H₃)methyl-9-methyl-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

(9R,13S)-13-{4-[2-(4-Bromo-1H-1,2,3-triazol-1-yl)-5-chlorophenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(²H₃)methyl-9-methyl-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one0.014 g, 0.022 mmol), prepared as described in Example 78,pyrimidin-2-ylboronic acid (2.59 mg, 0.021 mmol), and 2.0 M aq Na₂CO₃(0.033 mL, 0.066 mmol) were added to dioxane (0.6 ml) and the resultingsolution was purged with a stream of Ar. Pd(PPh₃)₄ (1.270 mg, 1.099μmol) was then added and the mixture was heated to 120° C. in amicrowave for 30 min. The reaction was concentrated and the residue wasdiluted with DMF, filtered and reconcentrated. The residue was purifiedby preparative LCMS using (5:95 ACN/H₂O to 95:5 ACN/H₂O, 10 mM NH₄OAc)to give(9R,13S)-13-(4-{5-chloro-2-[4-(pyrimidin-2-yl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(²H₃)methyl-9-methyl-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(2.5 mg, 25%). MS(ESI) m/z: 636.08 (M+H)⁺. ¹H NMR (400 MHz, CD₃OD) δ9.16-9.11 (m, 2H), 9.06 (s, 1H), 8.75-8.65 (m, 1H), 8.02 (s, 1H),7.85-7.77 (m, 1H), 7.71-7.63 (m, 1H), 7.63-7.58 (m, 2H), 7.45-7.35 (m,3H), 7.16 (s, 1H), 6.37-6.30 (m, 1H), 5.69 (d, J=9.2 Hz, 1H), 2.35 (s,1H), 2.18 (d, J=9.9 Hz, 1H), 1.95 (d, J=7.9 Hz, 1H), 1.73 (s, 1H), 1.44(d, J=9.5 Hz, 2H), 1.19 (m, 1H), 1.02 (d, J=6.8 Hz, 3H). Analytical HPLC(Method C) RT=1.43 min, purity=95%; Factor XIa Ki=1.0 nM, PlasmaKallikrein Ki=150 nM.

Example 80 Preparation of(10R,14S)-14-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-4,10-dimethyl-3,8-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-9-one

80A. Preparation of tert-butylN-[(1S)-1-[3-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)phenyl]but-3-en-1-yl]carbamate

To a RBF was added tert-butylN-[(1S)-1-(3-bromophenyl)but-3-en-1-yl]carbamate (2.6 g, 7.97 mmol),5,5,5′,5′-tetramethyl-2,2′-bi(1,3,2-dioxaborinane (1.980 g, 8.77 mmol),and KOAc (2.347 g, 23.91 mmol) in dioxane (35 ml). The mixture waspurged with Ar for 10 min, then PdCl₂(dppf)-DCM adduct (0.325 g, 0.398mmol) was added and the reaction was stirred at 90° C. for 4 h. Thereaction was partitioned between EtOAc (50 ml) and water (40 ml). Theorganic layer was separated, washed with water (15 ml), brine (30 ml),dried over MgSO₄, filtered and concentrated. The residue was purified bynormal phase chromatography using hexanes and EtOAc as eluents to affordtert-butylN-[(1S)-1-[3-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)phenyl]but-3-en-1-yl]carbamate(2.62 g, 92%) as a white solid. MS(ESI) m/z: 292.08 (M+H)⁺.

80B. Preparation of tert-butylN-[(1S)-1-[3-(3-amino-6-methylpyridin-2-yl)phenyl]but-3-en-1-yl]carbamate

tert-ButylN-[(1S)-1-[3-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)phenyl]but-3-en-1-yl]carbamate(0.67 g, 1.865 mmol), 2-bromo-6-methylpyridin-3-amine (0.349 g, 1.865mmol), and 2 M aq Na₂CO₃ (4 mL, 8.00 mmol) were added to dioxane (9 ml)and the solution was purged with a stream of Ar for 10 min. Pd(PPh₃)₄(0.108 g, 0.093 mmol) was added and the mixture was irradiated in amicrowave at 120° C. for 30 min. The reaction was quenched with water(20 ml) and extracted with EtOAc (3×30 ml). The combined organic layerswere washed with brine (15 ml), dried (MgSO₄), filtered andconcentrated. The residue was purified by normal phase chromatographyusing DCM and 0-10% MeOH as eluents to afford tert-butylN-[(1S)-1-[3-(3-amino-6-methylpyridin-2-yl)phenyl]but-3-en-1-yl]carbamate(0.94 g, 100%, 70% purity) as a brown oil. MS(ESI) m/z: 354.5 (M+H)⁺.

80C. Preparation of tert-butyl N-[(lS)-1-(3-{6-methyl-3-[(2R)-2-methylbut-3-enamido]pyridin-2-yl}phenyl)but-3-en-1-yl]carbamate

To a solution of tert-butylN-[(1S)-1-[3-(3-amino-6-methylpyridin-2-yl)phenyl]but-3-en-1-yl]carbamate(0.65 g, 1.83 mmol) in EtOAc (0.58 ml), was added(R)-2-methylbut-3-enoic acid (0.239 g, 2.391 mmol), prepared asdescribed in Intermediate 2, in 0.3 ml EtOAc. The resulting solution wascooled to 0° C. and pyridine (0.446 ml, 5.52 mmol) and a 50% EtOAcsolution of T3P® (2.189 ml, 3.68 mmol) were added. After 3 h, thereaction was quenched with sat NaHCO₃ (15 ml) and extracted with EtOAc(3×20 ml). The combined organic layers were washed with brine (15 ml)and dried (MgSO₄). The mixture was filtered and concentrated and theresidue was purified by normal phase chromatography using DCM and 0-10%MeOH as eluents to afford tert-butylN-[(1S)-1-(3-{6-Methyl-3-[(2R)-2-methylbut-3-enamido]pyridin-2-yl}phenyl)but-3-en-1-yl]carbamate(0.65 g, 82%) as a tan foam. MS(ESI) m/z: 436.08 (M+H)⁺. ¹H NMR (500MHz, CDCl₃) δ 8.56 (d, J=8.5 Hz, 1H), 7.54-7.46 (m, 2H), 7.42 (s, 1H),7.37 (d, J=1.4 Hz, 2H), 7.17 (d, J=8.5 Hz, 1H), 5.90-5.67 (m, 2H),5.22-5.03 (m, 4H), 5.00-4.75 (m, 3H), 3.05 (t, J=7.3 Hz, 1H), 2.62 (br.s. and m, 4H), 1.50-1.39 (m, 9H), 1.28 (d, J=7.2 Hz, 3H).

80D. Preparation of tert-butylN-[(10R,11E,14S)-4,10-dimethyl-9-oxo-3,8-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,11,15,17-heptaen-14-yl]carbamate

To a solution of tert-butylN-[(1S)-1-(3-{6-methyl-3-[(2R)-2-methylbut-3-enamido]pyridin-2-yl}phenyl)but-3-en-1-yl]carbamate(0.2 g, 0.459 mmol) in degassed DCE (20 ml) was added Second GenerationGrubbs Catalyst (0.156 g, 0.184 mmol) and the resulting reaction mixturewas heated to 120° C. for 30 min in a microwave. The reaction mixturewas directly purified by normal phase chromatography using DCM and 0-10%MeOH as eluents to afford tert-butylN-[(10R,11E,14S)-4,10-dimethyl-9-oxo-3,8-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,11,15,17-heptaen-14-yl]carbamate (0.19 g, 100%) as a darksolid. MS(ESI) m/z: 408.08 (M+H)⁺.

80E. Preparation of(10R,14S)-14-amino-4,10-dimethyl-3,8-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-9-one

tert-ButylN-[(10R,11E,14S)-4,10-dimethyl-9-oxo-3,8-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,11,15,17-heptaen-14-yl]carbamate(0.187 g, 0.459 mmol) was hydrogenated in EtOH (3 ml) in the presence ofPtO₂ at 20-30 psi. After 4 h, the reaction mixture was filtered throughCELITE® and concentrated to afford a dark solid (MS(ESI) m/z: 410.3(M+H)⁺) which was then deprotected with 4 N HCl in dioxane (2 ml) andMeOH (2 ml). The resultant HCl salt was dissolved in DCM/MeOH and passedthrough a basic cartridge to afford (0.16 g, 118%) of a crude dark solidcontaining as the major component,(10R,14S)-14-amino-4,10-dimethyl-3,8-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-9-one,which was used in next step without purification. MS(ESI) m/z: 310.3(M+H)⁺.

80F. Preparation of(10R,14S)-14-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-4,10-dimethyl-3,8-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,515,17-hexaen-9-one

To6-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}pyrimidin-4-ol(0.033 g, 0.097 mmol), prepared as described in Intermediate 15, andHATU (0.048 g, 0.126 mmol) in a small vial was added DBU (0.022 mL,0.145 mmol) in ACN (0.4 ml). After 30 min,(10R,14S)-14-amino-4,10-dimethyl-3,8-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-9-one(0.033 g, 0.097 mmol) was added with DMF (0.2 ml). The reaction wasstirred for 18 h. The reaction was diluted with DMF, filtered andpurified by preparative LCMS using (5:95 ACN/H₂O to 95:5 ACN/H₂O, 10 mMNH₄OAc) to afford(10R,14S)-14-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-4,10-dimethyl-3,8-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-9-one(5.8 mg, 7.7% yield) as a white solid. MS(ESI) m/z: 634.4 (M+H)⁺. ¹H NMR(500 MHz, CD₃OD) δ 8.75 (s, 1H), 8.12 (s, 1H), 7.86-7.82 (m, 2H),7.77-7.64 (m, 3H), 7.62-7.54 (m, 2H), 7.34 (d, J=8.2 Hz, 1H), 7.29 (d,J=7.9 Hz, 1H), 6.43 (s, 1H), 5.86-5.73 (m, 1H), 2.61 (s, 3H), 2.45 (br.s., 1H), 2.26 (d, J=9.5 Hz, 1H), 2.11 (br. s., 1H), 1.82 (br. s., 1H),1.64-1.49 (m, 2H), 1.28-1.21 (m, 1H), 1.13 (d, J=6.7 Hz, 3H). AnalyticalHPLC (Method C) RT=1.54 min, purity=97%; Factor XIa Ki=2.2 nM, PlasmaKallikrein Ki=260 nM.

Example 81 Preparation of(10R,14S)-14-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-5-methoxy-10-methyl-3,8-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-9-one

81A. Preparation of tert-butylN-[(1S)-1-[3-(3-amino-5-methoxypyridin-2-yl)phenyl]but-3-en-1-yl]carbamate

tert-ButylN-[(1S)-1-[3-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)phenyl]but-3-en-1-yl]carbamate(0.348 g, 0.969 mmol), 2-bromo-5-methoxypyridin-3-amine (0.197 g, 0.969mmol), and 2.0 M aq Na₂CO₃ (2.422 mL, 4.84 mmol) were added to dioxane(8 ml) and the solution was purged with a stream of Ar for 10 min.Pd(PPh₃)₄ (0.056 g, 0.048 mmol) was added and the mixture irradiated inmicrowave at 120° C. for 30 min. The reaction was quenched with water(20 ml) and extracted with EtOAc (3×30 ml). The combined organic layerswere washed with brine (15 ml), dried (MgSO₄), filtered andconcentrated. The residue was purified by normal phase chromatographyusing DCM and 0-10% MeOH as eluents to afford tert-butylN-[(1S)-1-[3-(3-amino-5-methoxypyridin-2-yl)phenyl]but-3-en-1-yl]carbamate (0.391 g, 100%) as a tan foam. MS(ESI)m/z: 370.08 (M+H)⁺. ¹H NMR (500 MHz, CDCl₃) δ 7.89 (d, J=2.5 Hz, 1H),7.60-7.52 (m, 2H), 7.45 (t, J=7.6 Hz, 1H), 7.33-7.29 (m, 1H), 6.62 (d,J=2.5 Hz, 1H), 5.73 (ddt, J=17.1, 10.1, 7.0 Hz, 1H), 5.21-5.06 (m, 2H),4.93 (br. s., 1H), 4.81 (br. s., 1H), 3.92-3.86 (m, 4H), 3.77-3.71 (m,1H), 2.64-2.52 (m, 2H), 1.44 (br. s., 9H).

81B. Preparation of tert-butyl N-[(1S)-1-(3-{5-methoxy-3-[(2R)-2-methylbut-3-enamido]pyridin-2-yl}phenyl)but-3-en-1-yl]carbamate

To tert-butylN-[(1S)-1-[3-(3-amino-5-methoxypyridin-2-yl)phenyl]but-3-en-1-yl]carbamate(0.358 g, 0.972 mmol) was added (R)-2-methylbut-3-enoic acid (0.126 g,1.263 mmol), prepared as described in Intermediate 2, in EtOAc (3 ml).The resulting solution was cooled to 0° C. Pyridine (0.236 ml, 2.91mmol) and a 50% EtOAc solution of T3P® (1.157 ml, 1.943 mmol) wereadded. The reaction was partitioned between sat NaHCO₃ (10 ml) and EtOAc(20 ml). The aqueous layer was extracted with EtOAc (2×20 ml). Thecombined organic layers were washed with brine (25 ml), dried (MgSO₄),filtered and concentrated. The residue was purified by normal phasechromatography using heptanes and EtOAc as eluents to afford tert-butylN-[(1S)-1-(3-{5-methoxy-3-[(2R)-2-methylbut-3-enamido]pyridin-2-yl}phenyl)but-3-en-1-yl]carbamate(0.347 g, 79%) as a white foam. MS(ESI) m/z: 452.08 (M+H)⁺. ¹H NMR (500MHz, CDCl₃) δ 8.47 (d, J=2.8 Hz, 1H), 8.16 (d, J=2.8 Hz, 1H), 7.65 (br.s., 1H), 7.53-7.46 (m, 1H), 7.46-7.41 (m, 1H), 7.37 (dt, J=7.5, 1.9 Hz,2H), 5.86-5.65 (m, 2H), 5.19-5.07 (m, 4H), 4.93 (br. s., 1H), 4.82 (br.s., 1H), 3.93 (s, 3H), 3.07 (quin, J=7.3 Hz, 1H), 2.62-2.51 (m, 2H),1.50-1.41 (m, 9H), 1.32-1.29 (m, 3H).

81C. Preparation of tert-butylN-[(10R,11E,14S)-5-methoxy-10-methyl-9-oxo-3,8-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,11,15,17-heptaen-14-yl]carbamate

A solution of tert-butyl N-[(1S)-1-(3-{5-methoxy-3-[(2R)-2-methylbut-3-enamido]pyridin-2-yl}phenyl)but-3-en-1-yl]carbamate(0.189 g, 0.419 mmol) in degassed DCE (20 ml) in the presence of SecondGeneration Grubbs Catalyst (0.107 g, 0.126 mmol) was heated to 120° C.for 30 min in a microwave. The reaction mixture was directly purified bynormal phase chromatography using DCM and 0-10% MeOH as eluents toafford tert-butylN-[(10R,11E,14S)-5-methoxy-10-methyl-9-oxo-3,8-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,11,15,17-heptaen-14-yl]carbamate (0.17 g, 96%) as a darkbrown oil. MS(ESI) m/z: 424.1 (M+H)⁺.

81D. Preparation of(10R,14S)-14-amino-5-methoxy-10-methyl-3,8-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-9-one

tert-ButylN-[(10R,11E,14S)-5-methoxy-10-methyl-9-oxo-3,8-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,11,15,17-heptaen-14-yl]carbamate(0.177 g, 0.418 mmol) was hydrogenated in EtOH (3 ml) in the presence ofPtO₂ (20 mg) over 8 h. The resultant thick sludge was filtered throughCELITE® and rinsed with DCM, MeOH and EtOH to afford 0.121 g of a darksolid. MS(ESI) m/z: 426.4 (M+H)⁺. Deprotection was performed with 4 NHCl in dioxane (2 ml) in MeOH (4 ml) over 3 h. The reaction mixture wasconcentrated and the residue was taken up in DCM/MeOH and filteredthrough a basic cartridge to give(10R,14S)-14-amino-5-methoxy-10-methyl-3,8-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-9-oneas a dark solid (0.108 g, 79%). MS(ESI) m/z: 326.4 (M+H)⁺.

81E. Preparation of(10R,14S)-14-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-5-methoxy-10-methyl-3,8-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-9-one

To6-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}pyrimidin-4-ol(0.032 g, 0.092 mmol), prepared as described in Intermediate 15, andHATU (0.046 g, 0.120 mmol) in a small vial was added DBU (0.021 mL,0.138 mmol) in ACN (0.4 ml). After 30 min,(10R,14S)-14-amino-5-methoxy-10-methyl-3,8-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-9-one(0.030 g, 0.092 mmol) was added with DMF (0.4 ml). After 18 h, thereaction was diluted with DMF, filtered and concentrated. The residuewas purified twice by reverse phase HPLC using PHENOMENEX® Luna 5U30×100 mm (10:90 ACN/H₂O to 90:10 ACN/H₂O, 0.1% TFA) (20% B start, 14min gradient) to afford(10R,14S)-14-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-5-methoxy-10-methyl-3,8-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-9-one (3.7 mg, 4.8%) as a white solid.MS(ESI) m/z: 650.3 (M+H)⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.82 (d, J=0.7 Hz,1H), 8.39 (d, J=2.6 Hz, 1H), 8.25 (s, 1H), 7.89 (d, J=2.2 Hz, 1H), 7.86(s, 1H), 7.80-7.74 (m, 1H), 7.71-7.63 (m, 2H), 7.62-7.55 (m, 2H), 7.29(d, J=7.9 Hz, 1H), 6.47 (d, J=0.7 Hz, 1H), 5.81 (dd, J=13.0, 3.5 Hz,1H), 4.03-4.01 (m, 3H), 2.60-2.49 (m, 1H), 2.34-2.26 (m, 1H), 2.18-2.08(m, 1H), 1.94-1.85 (m, 1H), 1.62-1.46 (m, 2H), 1.33 (d, J=9.7 Hz, 1H),1.15 (d, J=6.8 Hz, 3H). Analytical HPLC (Method A) RT=8.44, purity=93%;Factor XIa Ki=22 nM, Plasma Kallikrein Ki=950 nM.

Example 82 Preparation of(10R,14S)-5-chloro-14-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-10-methyl-3,8-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-9-one

82A. Preparation of tert-butylN-[(1S)-1-[3-(3-amino-5-chloropyridin-2-yl)phenyl]but-3-en-1-yl]carbamate

tert-ButylN-[(1S)-1-[3-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)phenyl]but-3-en-1-yl]carbamate(0.339 g, 0.944 mmol), 2-bromo-5-chloropyridin-3-amine (0.196 g, 0.944mmol), and 2.0 M aq Na₂CO₃ (2.36 mL, 4.72 mmol) were added to dioxane (8ml) and the resulting solution was purged with a stream of Ar for 10min. Pd(PPh₃)₄ (0.055 g, 0.047 mmol) was added and the mixtureirradiated on microwave at 120° C. for 30 min. The reaction was quenchedwith water (20 ml) and extracted with EtOAc (3×30 ml). The combinedorganic layers were washed with brine (15 ml), dried (Na₂SO₄), filteredand concentrated. The residue was purified by normal phasechromatography using DCM and 0-10% MeOH as eluents to afford tert-butylN-[(1S)-1-[3-(3-amino-5-chloropyridin-2-yl)phenyl]but-3-en-1-yl]carbamate (0.375 g, 106%) as a tan foam. MS(ESI)m/z: 374.3 (M+H)⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.08 (d, J=2.2 Hz, 1H),7.60-7.52 (m, 2H), 7.48-7.43 (m, 1H), 7.34 (d, J=7.7 Hz, 1H), 7.07 (d,J=1.9 Hz, 1H), 5.72 (ddt, J=17.1, 10.1, 7.0 Hz, 1H), 5.21-5.09 (m, 2H),4.93 (br. s., 1H), 4.81 (br. s., 1H), 3.94 (br. s., 2H), 2.63-2.51 (m,2H), 1.43 (br. s., 9H).

82B. Preparation of tert-butylN-[(1S)-1-(3-{5-chloro-3-[(2R)-2-methylbut-3-enamido]pyridin-2-yl}phenyl)but-3-en-1-yl]carbamate

To tert-butylN-[(1S)-1-[3-(3-amino-5-chloropyridin-2-yl)phenyl]but-3-en-1-yl]carbamate(0.358 g, 0.958 mmol) was added (R)-2-methylbut-3-enoic acid (0.125 g,1.245 mmol), prepared as described in Intermediate 2, in 3 ml EtOAc, andthe resulting solution was cooled to 0° C. Pyridine (0.232 ml, 2.87mmol) and a 50% EtOAc solution of T3P® (1.140 ml, 1.915 mmol) were thenadded. After 4 h, the reaction was partitioned with sat NaHCO₃ (10 ml)and EtOAc (10 ml). The aqueous layer was extracted with EtOAc (2×20 ml).The combined organic layers were washed with brine (10 ml), dried(Na₂SO₄), filtered and concentrated. The residue was purified by normalphase chromatography using heptanes and EtOAc as eluents to givetert-butylN-[(1S)-1-(3-{5-chloro-3-[(2R)-2-methylbut-3-enamido]pyridin-2-yl}phenyl)but-3-en-1-yl]carbamate(0.31 g, 71%) as a white foam. MS(ESI) m/z: 456.08 (M+H)⁺. ¹H NMR (500MHz, CDCl₃) δ 8.88 (d, J=2.2 Hz, 1H), 8.38 (d, J=2.2 Hz, 1H), 7.65 (br.s., 1H), 7.56-7.49 (m, 1H), 7.45-7.40 (m, 2H), 7.39-7.33 (m, 1H),5.82-5.66 (m, 2H), 5.21-5.11 (m, 2H), 5.11-5.06 (m, 2H), 4.93 (br. s.,1H), 4.82 (br. s., 1H), 3.08 (quin, J=7.2 Hz, 1H), 2.64-2.50 (m, 2H),1.46-1.41 (m, 9H), 1.30 (d, J=7.2 Hz, 3H).

82C. Preparation of tert-butylN-[(10R,11E,14S)-5-chloro-10-methyl-9-oxo-3,8-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,11,15,17-heptaen-14-yl]carbamate

A solution of Second Generation Grubbs Catalyst (0.107 g, 0.126 mmol)and tert-butylN-[(1S)-1-(3-{5-chloro-3-[(2R)-2-methylbut-3-enamido]pyridin-2-yl}phenyl)but-3-en-1-yl]carbamate(0.191 g, 0.419 mmol) in degassed DCE (20 ml) was heated to 120° C. for30 min in a microwave. The reaction mixture was concentrated and thecrude material was directly purified by normal phase chromatographyusing DCM and 0-10% MeOH as eluents to afford tert-butylN-[(10R,11E,14S)-5-chloro-10-methyl-9-oxo-3,8-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,11,15,17-heptaen-14-yl]carbamate(0.17 g, 95%) as a dark brown oil. MS(ESI) m/z: 428.2 (M+H)⁺.

82D. Preparation of(10R,14S)-14-amino-5-chloro-10-methyl-3,8-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-9-one

tert-ButylN-[(10R,11E,14S)-5-chloro-10-methyl-9-oxo-3,8-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,11,15,17-heptaen-14-yl]carbamate(0.17 g, 0.397 mmol) was hydrogenated in EtOH (3 ml) in the presence ofPtO₂ (20 mg) for 8 h. MS(ESI) m/z: 430.3 (M+H)⁺. The thick sludge wasfiltered through CELITE® and rinsed with DCM/MeOH/EtOH to afford 0.169 gof a dark solid. Deprotection was carried out with 4 N HCl in dioxane (2ml) and MeOH (2 ml) over 4 h. After this time the solution wasconcentrated and the residue was taken up in DCM/MeOH and passed througha basic cartridge to give(10R,14S)-14-amino-5-chloro-10-methyl-3,8-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-9-one as a crude product (0.159 g, 121%) thatwas used ‘as is’. MS(ESI) m/z: 330.08 (M+H)⁺.

82E. Preparation of(10R,14S)-5-chloro-14-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-10-methyl-3,8-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-9-one

To HATU (0.045 g, 0.118 mmol) and6-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}pyrimidin-4-ol(0.031 g, 0.091 mmol), prepared as described in Intermediate 15, in asmall vial was added DBU (0.021 mL, 0.136 mmol) in CH₃CN (0.4 ml). After30 min, tert-butylN-[(10R,11E,14S)-5-chloro-10-methyl-9-oxo-3,8-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,11,15,17-heptaen-14-yl]carbamate (0.030 g, 0.091 mmol) wasadded with DMF (0.4 ml). After 18 h, the reaction was diluted with DMF,filtered and concentrated The residue was purified twice by reversephase HPLC using PHENOMENEX® Luna 5U 30×100 mm (10:90 ACN/H₂O to 90:10ACN/H₂O, 0.1% TFA) (20% B start, 14 min gradient) to afford(10R,14S)-5-chloro-14-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-10-methyl-3,8-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-9-one(3.0 mg, 4.2% yield) as a tan solid. MS(ESI) m/z: 654.3 (M+H)⁺. ¹H NMR(400 MHz, CD₃OD) δ 8.81 (d, J=0.7 Hz, 1H), 8.67-8.62 (m, 1H), 8.23 (s,1H), 7.93-7.84 (m, 3H), 7.79-7.67 (m, 3H), 7.63-7.54 (m, 1H), 7.29 (d,J=7.9 Hz, 1H), 6.47 (d, J=0.9 Hz, 1H), 5.82 (dd, J=12.9, 3.6 Hz, 1H),2.58-2.48 (m, 1H), 2.40-2.24 (m, 1H), 2.11 (d, J=9.7 Hz, 1H), 1.99-1.87(m, 1H), 1.55 (d, J=9.0 Hz, 2H), 1.33 (d, J=9.7 Hz, 1H), 1.15 (d, J=6.8Hz, 3H). Analytical HPLC (Method A) RT=9.88 min, purity=98%; Factor XIaKi=3.5 nM, Plasma Kallikrein Ki=240 nM.

Example 83 Preparation of(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,16-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

83A. Preparation of tert-butylN-[(1S)-1-[5-(1-methyl-4-nitro-1H-pyrazol-5-yl)pyridin-3-yl]but-3-en-1-yl]carbamate

To a solution of tert-butylN-[(1S)-1-(5-bromopyridin-3-yl)but-3-en-1-yl]carbamate (1.0 g, 3.06mmol), prepared as described in Intermediate 26, in dioxane (10 ml) wasadded 1-methyl-4-nitro-1H-pyrazole (0.427 g, 3.36 mmol),di(adamantan-1-yl)(butyl)phosphine (0.164 g, 0.458 mmol), K₂C₀₃ (1.267g, 9.17 mmol) and pivalic acid (0.106 ml, 0.917 mmol). The reactionmixture was purged with Ar. Pd(OAc)₂ (0.069 g, 0.306 mmol) was added andthe solution was stirred at 100° C. After 4 h, the reaction was quenchedwith water (20 ml) and extracted with EtOAc (3×50 ml). The combinedorganic layers were washed with brine (20 ml), dried (MgSO₄), filtered,and concentrated. The residue was purified by normal phasechromatography using heptanes and EtOAc as eluents to give tert-butylN-[(1S)-1-[5-(1-methyl-4-nitro-1H-pyrazol-5-yl)pyridin-3-yl]but-3-en-1-yl]carbamate(0.85 g, 74%) as a white foam. MS(ESI) m/z: 374.5 (M+H)⁺. ¹H NMR (500MHz, CDCl₃) δ 8.74 (d, J=1.9 Hz, 1H), 8.57 (d, J=1.9 Hz, 1H), 8.25 (s,1H), 7.72 (t, J=1.9 Hz, 1H), 5.73 (ddt, J=17.1, 10.2, 7.2 Hz, 1H),5.26-5.17 (m, 2H), 4.99 (br. s., 1H), 4.93-4.84 (m, 1H), 3.80 (s, 3H),2.75-2.52 (m, 2H), 1.43 (br. s., 9H).

83B. Preparation of tert-butylN-[(1S)-1-[5-(4-amino-1-methyl-1H-pyrazol-5-yl)pyridin-3-yl]but-3-en-1-yl]carbamate

To a solution of tert-butylN-[(1S)-1-[5-(1-methyl-4-nitro-1H-pyrazol-5-yl)pyridin-3-yl]but-3-en-1-yl]carbamate (0.85 g, 2.276) in acetone (60ml)/water (15 ml) at 0° C. was added NH₄Cl (0.609 g, 11.38 mmol) and Zn(1.488 g, 22.76 mmol). The ice bath was removed and the reaction wasstirred 18 h. The reaction was filtered through paper and partitionedbetween water (20 ml) and EtOAc (75 ml). The aqueous layer was extractedwith EtOAc (2×50 ml). The combined organic layers were washed with brine(25 ml), dried (MgSO₄), filtered, and concentrated. The residue waspurified by normal phase chromatography using hexanes and EtOAc aseluents to give tert-butylN-[(1S)-1-[5-(4-amino-1-methyl-1H-pyrazol-5-yl)pyridin-3-yl]but-3-en-1-yl]carbamate(0.64 g, 65% yield). MS(ESI) m/z: 344.5 (M+H)⁺.

83C. Preparation of tert-butylN-[(1S)-1-(5-{1-methyl-4-[(2R)-2-methylbut-3-enamido]-1H-pyrazol-5-yl}pyridin-3-yl)but-3-en-1-yl]carbamate

To a solution of tert-butylN-[(1S)-1-(5-{1-methyl-4-[(2R)-2-methylbut-3-enamido]-1H-pyrazol-5-yl}pyridin-3-yl)but-3-en-1-yl]carbamate (0.5 g, 1.45 mmol) in EtOAc (4 ml) was added asolution of (R)-2-methylbut-3-enoic acid (0.189 g, 1.893 mmol), preparedas described in Intermediate 2, in 0.3 ml EtOAc. The reaction mixturewas cooled to 0° C. and pyridine (0.353 ml, 4.37 mmol) and a 50% EtOAcsolution of T3P® (1.733 ml, 2.91 mmol) were added. After 3 h, thereaction was partitioned between sat NaHCO₃ (15 ml) and EtOAc (20 ml).The aqueous layer was extracted with EtOAc (2×20 ml). The combinedorganic layers were washed with brine (10 ml), dried (MgSO₄), filteredand concentrated. The residue was purified by normal phasechromatography using DCM and 0-10% MeOH as eluents to give tert-butylN-[(1S)-1-(5-{1-methyl-4-[(2R)-2-methylbut-3-enamido]-1H-pyrazol-5-yl}pyridin-3-yl)but-3-en-1-yl]carbamate(0.48 g, 77% yield) as a pink solid. MS(ESI) m/z: 426.5 (M+H)⁺. ¹H NMR(500 MHz, CDCl₃) δ 8.66 (d, J=2.2 Hz, 1H), 8.51 (d, J=1.9 Hz, 1H), 7.99(s, 1H), 7.62 (t, J=2.1 Hz, 1H), 6.95 (br. s., 1H), 5.91 (ddd, J=17.2,10.0, 8.0 Hz, 1H), 5.79-5.66 (m, 1H), 5.25-5.13 (m, 4H), 4.95 (br. s.,1H), 4.82 (br. s., 1H), 3.85-3.77 (m, 3H), 3.10 (quin, J=7.2 Hz, 1H),2.68-2.51 (m, 2H), 1.50-1.37 (m, 9H), 1.37-1.29 (m, 3H).

83D. Preparation of tert-butylN-[(9R,10E,13S)-3,9-dimethyl-8-oxo-3,4,7,16-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate

To a solution of tert-butylN-[(1S)-1-(5-{1-methyl-4-[(2R)-2-methylbut-3-enamido]-1H-pyrazol-5-yl}pyridin-3-yl)but-3-en-1-yl]carbamate(0.153 g, 0.36 mmol) in DCM (90 ml) was added pTsOH.H₂O (0.075 g, 0.396mmol) and the mixture was degassed for 10 min, then heated to 40° C. for1 h. Second Generation Grubbs Catalyst (0.122 g, 0.144 mmol) was addedand the reaction was heated at 40° C. for 24 h. The reaction wasquenched with sat NaHCO₃ (15 ml) and extracted with DCM (3×20 ml). Thecombined organic layers were washed with brine (30 ml), dried (MgSO₄),filtered and concentrated. The residue purified by normal phasechromatography using DCM and MeOH as eluents to afford tert-butylN-[(9R,10E,13S)-3,9-dimethyl-8-oxo-3,4,7,16-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate(20 mg, 14%) as a brown solid. MS(ESI) m/z: 398.2 (M+H)⁺. ¹H NMR (500MHz, CDCl₃) δ 8.60 (s, 1H), 7.57 (s, 1H), 7.25-7.17 (m, 1H), 6.98 (s,1H), 6.52 (br. s., 1H), 5.78-5.65 (m, 1H), 5.14 (br. s., 1H), 5.04-4.96(m, 1H), 4.79 (br. s., 1H), 3.97 (s, 3H), 3.85-3.74 (m, 1H), 3.06 (br.s., 1H), 2.61 (br. s., 4H), 1.46 (br. s., 9H), 1.30-1.23 (m, 3H).

83E. Preparation of(9R,13S)-13-amino-3,9-dimethyl-3,4,7,16-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

tert-ButylN-[(9R,10E,13S)-3,9-dimethyl-8-oxo-3,4,7,16-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate(20 mg, 0.050 mmol) was hydrogenated in EtOH (3 ml) in the presence ofPtO₂ (4 mg) at 55 psi. After 4 h, the reaction mixture was filteredthrough CELITE® and concentrated to afford 16 mg of a dark solid(MS(ESI) m/z: 400.08 (M+H)⁺ which was then deprotected with 4 N HCl indioxane (1 ml) and MeOH (1 ml). After 3 h, the mixture was concentratedand the resultant HCl salt was dissolved in DCM/MeOH and passed througha basic cartridge to afford(9R,13S)-13-amino-3,9-dimethyl-3,4,7,16-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(15 mg, 100%) as a dark solid.

83F. Preparation of(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,16-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

To 6-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]pyrimidin-4-ol(0.015 g, 0.050 mmol), prepared as described in Intermediate 15, andHATU (0.025 g, 0.065 mmol) in a small vial was added DBU (0.011 mL,0.075 mmol) in CH₃CN (0.4 ml). After 30 min,(9R,13S)-13-amino-3,9-dimethyl-3,4,7,16-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(0.015 g, 0.050 mmol) was added with DMF (0.2 ml). After 18 h, thereaction was diluted with DMF, filtered and purified by reverse phaseHPLC using PHENOMENEX® Luna 5U 30×100 mm (10:90 ACN/H₂O to 90:10ACN/H₂O, 0.1% TFA) (20% B start, 14 min gradient) to afford(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,16-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(4.1 mg, 11%) as an off-white solid. MS(ESI) m/z: 590.3 (M+H)⁺. ¹H NMR(400 MHz, CD₃OD) δ 8.83 (d, J=1.8 Hz, 1H), 8.64 (d, J=2.0 Hz, 1H),8.42-8.34 (m, 2H), 8.30 (s, 1H), 7.95-7.86 (m, 1H), 7.81-7.72 (m, 1H),7.69-7.63 (m, 1H), 7.60-7.53 (m, 1H), 6.49-6.42 (m, 1H), 5.79 (dd,J=13.0, 3.1 Hz, 1H), 4.13 (s, 3H), 2.56-2.45 (m, 2H), 2.24-2.14 (m, 1H),1.89 (br. s., 1H), 1.65-1.53 (m, 2H), 1.23-1.14 (m, 3H), 1.10 (br. s.,1H). Analytical HPLC (Method A) rt=6.29 min, purity=98%; Factor XIaKi=0.2 nM, Plasma Kallikrein Ki=43 nM.

Example 84 Preparation of(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaene-16-carboxamide

84A. Preparation of3-bromo-5-[(1E)-{[(R)-2-methylpropane-2-sulfinyl]imino}methyl]benzamide

To 3-formylbenzonitrile (3.49 g, 26.6 mmol) in con. H₂SO₄ (12 ml) washeated to 60° C., NBS (5.68 g, 31.9 mmol) was added in 3 portions. Thereaction was stirred for 2 h. The reaction was quenched by pouring intoice water. The product was filtered off and dried. The collected crudeproduct was used ‘as is’ in next step. The crude material was combinedwith (R)-2-methylpropane-2-sulfinamide (1.382 g, 11.40 mmol), Cs₂CO₃(5.57 g, 17.10 mmol) in DCM (57.0 ml) and stirred 18 h. The reactionthickened to a gel, was diluted with DCM and stirring was resumed for 3h. The reaction was partitioned between brine (40 ml) and DCM (50 ml).The insoluble gel was filtered off. The aqueous layer was extracted withDCM (2×20 ml). The combined organic layers were dried (Na₂SO₄), filteredand concentrated. The residue was purified by normal phasechromatography using heptanes and EtOAc as eluents to afford3-bromo-5-[(1E)-{[(R)-2-methylpropane-2-sulfinyl]imino}methyl]benzamide(3.3 g). ¹H NMR (400 MHz, DMSO-d₆) δ 8.58 (s, 1H), 8.42 (s, 1H), 8.34(br. s., 1H), 8.26 (s, 2H), 7.68 (br. s., 1H), 1.20 (s, 9H).

84B. Preparation of3-bromo-5-[(1S)-1-{[(R)-2-methylpropane-2-sulfinyl]amino}but-3-en-1-yl]benzamide

To3-bromo-5-[(1E)-{[(R)-2-methylpropane-2-sulfinyl]imino}methyl]benzamide(3.3 g, 9.96 mmol) in THF (75 ml) was added In (1.716 g, 14.94 mmol) and3-bromoprop-1-ene (1.30 ml, 14.94 mmol). The reaction was stirred at rt.After, 72 h, the reaction became a gray suspension and LCMS showed itwas not complete. An additional 4 g of In and 2.6 ml of3-bromoprop-1-ene were added. After an additional week the reaction wasfiltered and the filtrate concentrated to give 4 g of crude3-bromo-5-[(1S)-1-{[(R)-2-methylpropane-2-sulfinyl]amino}but-3-en-1-yl]benzamide.MS(ESI) m/z: 373-375.1 (M+H)⁺.

84C. Preparation of tert-butylN-[(1S)-1-(3-bromo-5-carbamoylphenyl)but-3-en-1-yl]carbamate

To3-bromo-5-[(1S)-1-{[(R)-2-methylpropane-2-sulfinyl]amino}but-3-en-1-yl]benzamide(3.7 g, 9.91 mmol) in (1:1) dioxane/MeOH (50 ml) was added 15 ml ofconc. HCl. The reaction was stirred for 24 h, then concentrated. Theresidue was dissolved in DCM (50 ml) and cooled to 0° C. TEA (8.29 ml,59.5 mmol) and BOC₂O (2.301 ml, 9.91 mmol) were added. An additionalamount of 1 N NaOH was added to ensure reaction was basic. After 24 h,the thick reaction was filtered giving a gummy solid. Both the gummysolid and filtrate were combined and partitioned between water (100 ml)and EtOAc (150 ml). The aqueous layer was extracted with EtOAc (2×50ml). The combined organic layers were washed with brine (50 ml), dried(Na₂SO₄), filtered and concentrated. The residue was purified by normalphase chromatography using hexanes and EtOAc as eluents to affordtert-butyl N-[(1S)-1-(3-bromo-5-carbamoylphenyl)but-3-en-1-yl]carbamate(0.92 g, 25%). MS(ESI) m/z: 311-313.3 (M+H-t-butyl)⁺. ¹H NMR (400 MHz,CDCl₃) δ 7.88-7.79 (m, 1H), 7.74 (br. s., 1H), 7.56 (t, J=1.5 Hz, 1H),6.66 (br. s., 1H), 6.40 (br. s., 1H), 5.74-5.59 (m, 1H), 5.28-5.19 (m,1H), 5.17-5.12 (m, 1H), 4.71 (br. s., 1H), 2.57-2.45 (m, 3H), 1.49-1.34(m, 9H).

84D. Preparation of tert-butylN-[(1S)-1-{3-carbamoyl-5-[1-(difluoromethyl)-4-nitro-1H-pyrazol-5-yl]phenyl}but-3-en-1-yl]carbamate

To a solution of (S)-tert-butyl(1-(3-bromo-5-carbamoylphenyl)but-3-en-1-yl)carbamate (0.2 g, 0.542mmol) in dioxane (3 ml) was added 1-(difluoromethyl)-4-nitro-1H-pyrazole(0.106 g, 0.650 mmol), di(adamantan-1-yl)(butyl)phosphine (0.029 g,0.081 mmol), K₂CO₃ (0.225 g, 1.625 mmol) and pivalic acid (0.019 ml,0.162 mmol). The reaction was purged with Ar. Afterwards, Pd(OAc)₂(0.012 g, 0.054 mmol) was added and the reaction was heated to 100° C.After 18 h, the reaction was partitioned with water (20 ml) and EtOAc(20 ml) and filtered. The filtrate was extracted with EtOAc (2×20 ml).The combined organic layers were washed with brine (15 ml), dried(MgSO₄), filtered, and concentrated. The residue was purified by normalphase chromatography using heptanes and EtOAc as eluents to affordtert-butylN-[(1S)-1-{3-carbamoyl-5-[1-(difluoromethyl)-4-nitro-1H-pyrazol-5-yl]phenyl}but-3-en-1-yl]carbamate(0.177 g, 72.4%) as a yellow oil. MS(ESI) m/z: 450.1 (M−H)⁺. ¹H NMR (500MHz, CDCl₃) δ 8.34 (s, 1H), 7.99-7.91 (m, 1H), 7.85-7.77 (m, 1H),7.58-7.52 (m, 1H), 7.16-6.82 (m, 1H), 6.07 (br. s., 1H), 5.75-5.55 (m,2H), 5.20-5.08 (m, 2H), 4.96 (br. s., 1H), 4.82 (br. s., 1H), 2.62-2.46(m, 2H), 1.40 (d, J=7.2 Hz, 9H).

84E. Preparation of tert-butylN-[(1S)-1-{3-carbamoyl-5-[1-(difluoromethyl)-4-[(2R)-2-methylbut-3-enamido]-1H-pyrazol-5-yl]phenyl}but-3-en-1-yl]carbamate

To tert-butylN-[(1S)-1-{3-carbamoyl-5-[1-(difluoromethyl)-4-nitro-1H-pyrazol-5-yl]phenyl}but-3-en-1-yl]carbamate(0.177 g, 0.392 mmol) in acetone (40 ml)/water (12 ml), cooled to 0° C.,was added NH₄Cl (0.105 g, 1.960 mmol) and Zn (0.256 g, 3.92 mmol). After18 h at rt, the reaction was filtered through paper and the filtrate waspartitioned with water (20 ml) and EtOAc (25 ml). The aqueous layer wasextracted with EtOAc (2×25 ml). The combined organic layers were washedwith brine (25 ml), dried (MgSO₄) filtered and concentrated. To thecrude yellow oil in EtOAc (3 ml) at 0° C., was added(R)-2-methylbut-3-enoic acid (0.051 g, 0.510 mmol), prepared asdescribed in Intermediate 2, pyridine (0.095 mL, 1.176 mmol) and a 50%EtOAc solution of T3P® (0.233 mL, 0.784 mmol). After 24 h, the reactionwas partitioned between sat NaHCO₃ (10 ml) and EtOAc (20 ml). Theaqueous layer was extracted with EtOAc (2×20 ml). The combined organiclayers were washed with brine (25 ml), dried (MgSO₄), filtered andconcentrated. The was residue was purified by normal phasechromatography using hexanes and EtOAc as eluents to afford tert-butylN-[(1S)-1-{3-carbamoyl-5-[1-(difluoromethyl)-4-[(2R)-2-methylbut-3-enamido]-1H-pyrazol-5-yl]phenyl}but-3-en-1-yl]carbamate(0.113 g, 57%) as a yellow oil. MS(ESI) m/z: 448.3 (M+H-t-butyl)⁺.

84F. Preparation of tert-butylN-[(9R,10E,13S)-16-carbamoyl-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate

To a solution of tert-butylN-[(1)-1-{3-carbamoyl-5-[1-(difluoromethyl)-4-[(2R)-2-methylbut-3-enamido]-1H-pyrazol-5-yl]phenyl}but-3-en-1-yl]carbamate(0.113 g, 0.224 mmol) in degassed DCE (11 ml) was added SecondGeneration Grubbs Catalyst (0.08 g, 0.094 mmol) and the resultingsolution was heated to 120° C. for 30 min in a microwave. The reactionwas directly purified by normal phase chromatography using DCM and 0-10%MeOH as eluents gave tert-butylN-[(9R,10E,13S)-16-carbamoyl-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate(33 mg, 31%) as a tan solid. MS(ESI) m/z: 420.2 (M+H-t-butyl)⁺. ¹H NMR(400 MHz, CD₃OD) δ 7.95 (s, 1H), 7.82-7.78 (m, 2H), 7.10 (s, 1H), 5.73(ddd, J=15.2, 10.5, 4.7 Hz, 1H), 4.65 (d, J=9.5 Hz, 1H), 4.54 (dd,J=15.2, 9.2 Hz, 1H), 3.19-3.09 (m, 1H), 2.70 (dt, J=12.1, 3.5 Hz, 1H),2.03 (q, J=11.4 Hz, 1H), 1.46 (br. s., 9H), 1.08 (d, J=6.8 Hz, 3H).

84G. Preparation of(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaene-16-carboxamide

tert-ButylN-[(9R,10E,13S)-16-carbamoyl-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate(0.033 g, 0.069 mmol) was hydrogenated in EtOH (1 ml) in the presence ofPtO₂ (5 mg). After 4 h, the reaction was filtered through 0.45 μM filterto afford 0.022 g of a tan solid. MS(ESI) m/z: 422.3 (M+H-t-butyl)⁺. Theintermediate was deprotected in MeOH (1 ml) with 4 N HCl in dioxane (0.5ml). After 3 h, the reaction was concentrated. The residue was taken upin DCM/MeOH and passed through a basic cartridge and concentrated toafford(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaene-16-carboxamide(22 mg, 84%) as a brown solid. MS(ESI) m/z: 378.2 (M+H)⁺.

84H. Preparation of(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaene-16-carboxamide

To 6-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]pyrimidin-4-ol(0.018 g, 0.058 mmol), prepared as described in Intermediate 9, and HATU(0.029 g, 0.076 mmol) in a small vial was added DBU (0.013 mL, 0.087mmol) in ACN (0.4 ml). After 30 min,(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaene-16-carboxamide(0.022 g, 0.058 mmol) was added with DMF (0.2 ml). After 18 h, thereaction was diluted with DMF, filtered and purified by reverse phaseHPLC using PHENOMENEX® Luna 5U 30×100 mm (10:90 ACN/H₂O to 90:10ACN/H₂O, 0.1% TFA) (20% B start, 14 min gradient) to afford(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaene-16-carboxamide(10 mg, 25%) as a white solid. MS(ESI) m/z: 668.3 (M+H)⁺. ¹H NMR (400MHz, CD₃OD) δ 8.36 (s, 1H), 8.30 (s, 1H), 8.04 (s, 1H), 7.96 (s, 1H),7.91-7.86 (m, 2H), 7.85-7.78 (m, 1H), 7.77-7.71 (m, 1H), 7.70-7.63 (m,2H), 6.47-6.40 (m, 1H), 5.84 (dd, J=12.9, 3.4 Hz, 1H), 2.52 (ddd,J=10.0, 6.7, 3.5 Hz, 1H), 2.47-2.38 (m, 1H), 2.21-2.11 (m, 1H),1.98-1.86 (m, 1H), 1.67-1.47 (m, 2H), 1.22 (d, J=6.8 Hz, 1H), 1.16 (d,J=6.8 Hz, 3H). Analytical HPLC (Method A) RT=7.39 min, purity=98%;Factor XIa Ki=0.1 nM, Plasma Kallikrein Ki=18 nM.

Example 85 Preparation of1-(4-chloro-2-{1-[(9R,13S)-3-(²H₃)methyl-9-methyl-8-oxo-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)-1H-1,2,3-triazole-4-carboxamide

85A. Preparation of1-[4-chloro-2-(6-hydroxypyrimidin-4-yl)phenyl]-1H-1,2,3-triazole-4-carboxamide

To a suspension of1-[4-chloro-2-(6-methoxypyrimidin-4-yl)phenyl]-1H-1,2,3-triazole-4-carboxamide(60 mg, 0.18 mmol) in ACN (1 ml) was added TMSI (12 μL, 0.88 mmol). Thesolution was heated at 70° C. for 3 h. The reaction was cooled to rt andpoured into a 10% Na₂S₂O₃ solution. The insoluble yellow solid thatformed was filtered and washed with water to give crude1-[4-chloro-2-(6-hydroxypyrimidin-4-yl)phenyl]-1H-1,2,3-triazole-4-carboxamide(30 mg, 41.8% yield). MS(ESI) m/z: 317.3 (M+H)⁺. ¹H NMR (400 MHz, CD₃OD)δ 8.57 (s, 1H), 8.02 (s, 1H), 7.85 (d, J=2.4 Hz, 1H), 7.76-7.71 (m, 1H),7.70-7.64 (m, 1H), 6.39 (s, 1H).

85B. Preparation of1-(4-chloro-2-{1-[(9R,13S)-3-(²H₃)methyl-9-methyl-8-oxo-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)-1H-1,2,3-triazole-4-carboxamide

To1-[4-chloro-2-(6-hydroxypyrimidin-4-yl)phenyl]-1H-1,2,3-triazole-4-carboxamide(0.004 g, 0.013 mmol) and HATU (6.24 mg, 0.016 mmol) in a small vial wasadded DBU (2.86 μl, 0.019 mmol) in CH₃CN (0.8 ml). After 30 min, solid(9R,13S)-13-amino-3-(²H₃)methyl-9-methyl-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(0.038 g, 0.013 mmol), prepared as described in Intermediate 16, wasadded (rinsed with 0.2 ml DMF). The reaction was stirred 18 h, thendiluted with DMF, filtered and concentrated. The residue was purified bypreparative LCMS using (5:95 ACN/H₂O to 95:5 ACN/H₂O, 10 mM NH₄OAc) toafford1-(4-chloro-2-{1-[(9R,13S)-3-(²H₃)methyl-9-methyl-8-oxo-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)-1H-1,2,3-triazole-4-carboxamide(3.1 mg, 38% yield) as a white solid. MS(ESI) m/z: 601.08 (M+H)⁺. ¹H NMR(500 MHz, CD₃OD) δ 8.47-8.41 (m, 1H), 8.03 (s, 1H), 7.76 (d, J=2.2 Hz,1H), 7.67-7.60 (m, 2H), 7.60-7.53 (m, 1H), 7.52-7.41 (m, 2H), 7.41-7.36(m, 1H), 7.19 (d, J=7.4 Hz, 1H), 6.37-6.28 (m, 1H), 5.69 (d, J=9.6 Hz,1H), 4.45 (br. s., 1H), 2.40-2.34 (m, 1H), 2.27-2.19 (m, 1H), 1.82-1.73(m, 1H), 1.52-1.41 (m, 2H), 1.15-1.10 (m, 1H), 1.07-1.01 (m, 3H).Analytical HPLC (Method C) RT=1.31 min, purity=95%; Factor XIa Ki=0.3nM, Plasma Kallikrein Ki=60 nM.

Example 86 Preparation of(9R,13S)-13-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

86A. Preparation of4-nitro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole

To a solution of 4-nitro-1H-pyrazole (5.1 g, 45.1 mmol) in THF (50 mL)at 0° C. was added N-cyclohexyl-N-methylcyclohexanamine (19.32 mL, 90mmol) followed by dropwise addition of SEM-Cl (12 mL, 67.7 mmol). Thereaction mixture was slowly allowed to warm to rt and stirred for 18 h.The reaction mixture was concentrated and the residue was purified bynormal phase chromatography using hexanes and EtOAc as eluents to afford4-nitro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole (4.6 g, 43%yield) as a yellow oil. MS(ESI) m/z: 244 (M−H)⁺. ¹H NMR (500 MHz, CD₃Cl)δ 8.30 (s, 1H), 8.10 (s, 1H), 5.45 (s, 2H), 3.67-3.57 (m, 2H), 1.01-0.90(m, 2H), 0.04-0.00 (m, 9H).

86B. Preparation of tert-butylN-[(1S)-1-[3-(4-nitro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazol-5-yl)phenyl]but-3-en-1-yl]carbamate

To a solution of tert-butylN-[(1S)-1-(3-bromophenyl)but-3-en-1-yl]carbamate (0.4 g, 1.226 mmol) inDMF (3.07 ml) was added di(adamantan-1-yl)(butyl)phosphine (0.066 g,0.184 mmol), 4-nitro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole(0.298 g, 1.226 mmol), K₂CO₃ (0.508 g, 3.68 mmol) and pivalic acid(0.043 ml, 0.368 mmol). The reaction was purged with Ar for 10 min,then, Pd(OAc)₂ (0.028 g, 0.123 mmol) was added and the reaction washeated to 115° C. for 3 h. The reaction mixture was diluted withEtOAc/water and filtered through paper to remove Pd. The filtrate wasextracted (2×20 ml) EtOAc. The combined organic layer was washed withwater (15 ml), brine (15 ml), dried (MgSO₄), filtered and concentrated.The residue was purified by normal phase chromatography using hexanesand EtOAc as eluents to afford tert-butylN-[(1S)-1-[3-(4-nitro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazol-5-yl)phenyl]but-3-en-1-yl]carbamate(0.315 g, 53%) as a yellow oil. MS(ESI) m/z: 487.3 (M−H)⁺. ¹H NMR (500MHz, CD₃Cl) δ 8.23 (s, 1H), 7.53-7.40 (m, 4H), 5.69 (ddt, J=17.1, 10.1,7.2 Hz, 1H), 5.25 (s, 2H), 5.17-5.10 (m, 2H), 4.90 (br. s., 1H), 4.81(br. s., 1H), 3.75-3.64 (m, 2H), 2.55 (br. s., 2H), 1.48 (br. s., 9H),0.96-0.88 (m, 2H), 0.07-0.02 (m, 9H).

86C. Preparation of tert-butylN-[(1S)-1-[3-(4-amino-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazol-5-yl)phenyl]but-3-en-1-yl]carbamate

tert-ButylN-[(1S)-1-[3-(4-nitro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazol-5-yl)phenyl]but-3-en-1-yl]carbamate (0.315 g, 0.645 mmol) was dissolved inacetone (40 ml)/water (12 ml), cooled to 0° C. NH₄Cl (0.172 g, 3.22mmol) and Zn (0.421 g, 6.45 mmol) were added. The ice bath was removed.After 3 h, the reaction was partitioned with water (20 ml) and EtOAc (75ml) and filtered through paper. The aqueous layer was extracted withEtOAc (2×50 ml). The combined organic layers were washed with brine (25ml), dried (MgSO₄), filtered and concentrated. The residue was purifiedby normal phase chromatography using hexanes and EtOAc as eluents toafford tert-butylN-[(1S)-1-[3-(4-amino-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazol-5-yl)phenyl]but-3-en-1-yl]carbamate(0.269 g, 91%) as a yellow oil. MS(ESI) m/z: 459.5 (M−H)⁺. ¹H NMR (400MHz, CDCl₃) δ 7.54-7.42 (m, 3H), 7.34-7.28 (m, 2H), 5.72 (ddt, J=17.0,10.1, 7.0 Hz, 1H), 5.33-5.26 (m, 2H), 5.18-5.07 (m, 2H), 4.95 (br. s.,1H), 4.81 (br. s., 1H), 3.73-3.60 (m, 2H), 3.03 (br. s., 2H), 2.63-2.52(m, 2H), 1.50-1.36 (m, 9H), 0.97-0.88 (m, 2H), 0.04-0.03 (m, 9H).

86D. Preparation of tert-butylN-[(1S)-1-(3-{4-[(2R)-2-methylbut-3-enamido]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazol-5-yl)}phenyl)but-3-en-1-yl]carbamate

To tert-butylN-[(1S)-1-[3-(4-amino-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazol-5-yl)phenyl]but-3-en-1-yl]carbamate(0.269 g, 0.586 mmol) in EtOAc (1 ml) was added (R)-2-methylbut-3-enoicacid (0.076 g, 0.762 mmol), prepared as described in Intermediate 2, in1 mL EtOAc and the solution was cooled to 0° C. To the reaction mixturewas added pyridine (0.142 ml, 1.759 mmol) and 50% EtOAc solution of T3P®(0.698 ml, 1.173 mmol). After 1 h, the reaction was partitioned betweensat NaHCO₃ (10 ml) and EtOAc (30 ml). The aqueous layer was extractedwith EtOAc (2×20 ml). The combined organic layers were washed with brine(10 ml), dried (MgSO₄), filtered and concentrated. The residue waspurified by normal phase chromatography using hexanes and EtOAc aseluents to afford tert-butylN-[(1S)-1-(3-{4-[(2R)-2-methylbut-3-enamido]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazol-5-yl)}phenyl)but-3-en-1-yl]carbamate(0.241 g, 76%) as a pink oil. MS(ESI) m/z: 541.6 (M−H)⁺. ¹H NMR (400MHz, CDCl₃) δ 8.18 (s, 1H), 7.53-7.41 (m, 2H), 7.41-7.35 (m, 2H), 7.18(br. s., 1H), 5.92 (ddd, J=17.2, 10.1, 7.9 Hz, 1H), 5.81-5.65 (m, 1H),5.37-5.30 (m, 2H), 5.25-5.10 (m, 4H), 4.93 (br. s., 1H), 4.82-4.73 (m,1H), 3.75-3.66 (m, 2H), 3.12 (quin, J=7.2 Hz, 1H), 2.63-2.49 (m, 2H),1.48-1.39 (m, 9H), 1.35-1.31 (m, 3H), 1.00-0.90 (m, 2H), 0.03-0.02 (m,9H).

86E. Preparation of tert-butylN-[(9R,10E,13S)-9-methyl-8-oxo-3-{[2-(trimethylsilyl)ethoxy]methyl}-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate

A solution of tert-butylN-[(1S)-1-(3-{4-[(2R)-2-methylbut-3-enamido]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazol-5-yl}phenyl)but-3-en-1-yl]carbamate (0.241 g,0.446 mmol) in DCM (55 ml), purged with Ar for 15 min. Second GenerationGrubbs Catalyst (0.151 g, 0.178 mmol) was added and the reaction washeated to 40° C. After 24 h, the reaction mixture was concentrated andthe residue was purified by normal phase chromatography using DCM and0-10% MeOH and then, again with hexanes and EtOAc as eluents to affordtert-butyl N-[(9R,10E,13S)-9-methyl-8-oxo-3-{[2-(trimethylsilyl)ethoxy]methyl}-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate(0.224 g, 98%) as a dark solid. MS(ESI) m/z: 513.5 (M+H)⁺.

86F. Preparation of tert-butylN-[(9R,13S)-9-methyl-8-oxo-3-{[2-(trimethylsilyl)ethoxy]methyl}-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate

tert-ButylN-[(9R,10E,13S)-9-methyl-8-oxo-3-{[2-(trimethylsilyl)ethoxy]methyl}-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate(0.16 g, 0.312 mmol) was hydrogenated at 55 psi in EtOH (4 ml), in thepresence of PtO₂ (7.09 mg, 0.031 mmol). After 3 h, the reaction wasfiltered through CELITE® and concentrated to afford tert-butylN-[(9R,13S)-9-methyl-8-oxo-3-{[2-(trimethylsilyl)ethoxy]methyl}-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate(0.15 g, 93%) desired product as a gray solid. MS(ESI) m/z: 515.5(M+H)⁺.

86G. and 86H. Preparation of(9R,13S)-13-amino-9-methyl-3-{[2-(trimethylsilyl)ethoxy]methyl}-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one,and(9R,13S)-13-amino-9-methyl-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

tert-ButylN-[(9R,13S)-9-methyl-8-oxo-3-{[2-(trimethylsilyl)ethoxy]methyl}-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamat(0.15 g, 0.291 mmol) was heated in water (10 ml) in a microwave for 30min at 150° C. The water was decanted from a tarry material andfreeze-dried to afford a mixture of(9R,13S)-13-amino-9-methyl-3-{[2-(trimethylsilyl)ethoxy]methyl}-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(MS(ESI) m/z: 415.5 (M+H)⁺)) and(9R,13S)-13-amino-9-methyl-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-oneone (MS(ESI) m/z: 285.5 (M+H)⁺) (29 mg) which was carried on to the nextstep ‘as is’.

86I. Preparation of(9R,13S)-13-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

To6-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]pyrimidin-4-ol(0.015 g, 0.046 mmol), prepared as described in Intermediate 10, andHATU (0.023 g, 0.059 mmol) in a small vial was added DBU (10.34 μl,0.069 mmol) in CH₃CN (0.8 ml). After 30 min, the mixture of(9R,13S)-13-amino-9-methyl-3-{[2-(trimethylsilyl)ethoxy]methyl}-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-oneand(9R,13S)-13-amino-9-methyl-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one (13 mg) in DMF (0.8 ml) was added and the reactionwas stirred for 24 h. The reaction was diluted with DMF, filtered andpurified by reverse phase HPLC using PHENOMENEX® Luna 5U 30×100 mm(10:90 MeOH/H₂O to 90:10 MeOH/H₂O, 0.1% TFA) (25% B start, 14 mingradient) to afford(9R,13S)-13-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(2 mg, 7% yield) as a white solid. MS(ESI) m/z: 593.4 (M+H)⁺. ¹H NMR(400 MHz, CD₃OD) δ 8.29 (s, 1H), 8.11 (s, 1H), 7.91-7.82 (m, 2H),7.70-7.65 (m, 1H), 7.62 (s, 1H), 7.56-7.46 (m, 3H), 7.10 (d, J=7.5 Hz,1H), 6.67-6.62 (m, 1H), 5.93-5.86 (m, 1H), 2.65-2.57 (m, 1H), 2.29 (d,J=11.4 Hz, 1H), 2.11 (d, J=10.3 Hz, 1H), 1.98 (br. s., 1H), 1.65 (d,J=5.9 Hz, 1H), 1.59-1.50 (m, 1H), 1.40 (br. s., 1H), 1.15 (d, J=6.8 Hz,3H). Analytical HPLC (Method A) RT=7.38 min, purity=90%; Factor XIaKi=1.8 nM, Plasma Kallikrein Ki=90 nM.

Example 87 Preparation of(9R,13S)-13-{4-[3-chloro-2-fluoro-6-(1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate

(9R,13S)-13-{4-[3-Chloro-2-fluoro-6-(1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate was prepared in a similar manner as the proceduresdescribed in Example 56, by using6-(3-chloro-2-fluoro-6-(1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol(0.034 g, 0.116 mmol), prepared as described in Intermediate 7, and(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(0.039 g, 0.116 mmol), prepared as described in Intermediate 30, toyield(9R,13S)-13-{4-[3-chloro-2-fluoro-6-(1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate. MS(ESI) m/z: 610.2 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD) δ8.57 (s, 1H), 8.43 (d, J=5.2 Hz, 1H), 7.87 (d, J=1.1 Hz, 1H), 7.53 (dd,J=8.5, 7.7 Hz, 1H), 7.50-7.41 (m, 3H), 7.39-7.32 (m, 2H), 7.25-7.18 (m,3H), 6.22 (s, 1H), 5.75-5.65 (m, 1H), 2.43-2.35 (m, 1H), 2.01-1.91 (m,1H), 1.76-1.64 (m, 8H), 1.32-1.22 (m, 1H), 1.21-1.10 (m, 1H), 0.67 (d,J=7.2 Hz, 3H). Analytical HPLC (Method A): RT=7.59 min, purity=97.5%;Factor XIa Ki=0.22 nM, Plasma Kallikrein Ki=42 nM.

Example 88 Preparation of(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate

(9R,13S)-13-{4-[5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate was prepared in a similar manner as the proceduresdescribed in Example 56, by using6-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol(0.019 g, 0.062 mmol), prepared as described in Intermediate 9, and(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(0.021 g, 0.062 mmol), prepared as described in Intermediate 30, toyield(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate. MS(ESI) m/z: 626.2 [M+H]+. ¹H NMR (500 MHz, CD₃OD) δ8.91-8.83 (m, 1H), 8.78-8.71 (m, 1H), 8.33 (s, 1H), 7.88 (d, J=2.5 Hz,1H), 7.74 (s, 2H), 7.69-7.67 (m, 1H), 7.65 (s, 1H), 7.63 (t, J=58 Hz,1H), 7.52-7.50 (m, 1H), 6.36 (d, J=0.8 Hz, 1H), 6.06-5.95 (m, 1H),2.76-2.65 (m, 1H), 2.36-2.21 (m, 1H), 2.08-1.93 (m, 2H), 1.63-1.53 (m,1H), 1.53-1.42 (m, 1H), 0.99 (d, J=6.9 Hz, 3H). Analytical HPLC (MethodA): RT=8.87 min, purity=99.7%; Factor XIa Ki=0.12 nM, Plasma KallikreinKi=30 nM.

Example 89 Preparation of(9R,13S)-13-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one;trifluoroacetate

(9R,13S)-13-{4-[3-Chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate was prepared in a similar manner as the proceduresdescribed in Example 56, by using6-(3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl)pyrimidin-4-ol(0.025 g, 0.063 mmol), prepared as described in Intermediate 10, and(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(0.021 g, 0.063 mmol), prepared as described in Intermediate 30, toyield(9R,13S)-13-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate. MS(ESI) m/z: 644.3 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ8.92-8.84 (m, 1H), 8.80-8.72 (m, 1H), 8.32 (s, 1H), 7.89-7.82 (m, 1H),7.75 (s, 1H), 7.74-7.70 (m, 1H), 7.66 (t, J=58 Hz, 1H), 7.54 (d, J=1.5Hz, 2H), 6.60 (s, 1H), 6.07-5.97 (m, 1H), 2.76-2.65 (m, 1H), 2.36-2.23(m, 1H), 2.09-1.96 (m, 2H), 1.65-1.42 (m, 2H), 1.00 (d, J=7.0 Hz, 3H).Analytical HPLC (Method A): RT=8.36 min, purity=98.8%; Factor XIa Ki=0.1nM, Plasma Kallikrein Ki=11 nM.

Example 90 Preparation of(9R,13S)-13-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(2-hydroxyethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate

(9R,13S)-13-{4-[3-Chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(2-hydroxyethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate was prepared in a similar manner as the proceduresdescribed in Example 56, by using6-(3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl)pyrimidin-4-ol(0.054 g, 0.167 mmol), prepared as described in Intermediate 10, and(9R,13S)-13-amino-3-(2-hydroxyethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one (0.055 g, 0.167 mmol), prepared asdescribed in Intermediate 40. The crude product was purified by prepHPLC to give(9R,13S)-13-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(2-hydroxyethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate. (45 mg, 34% yield) as tan solid. ¹H NMR (400 MHz,CD₃OD) δ 8.82 (s, 1H), 8.75 (d, J=5.3 Hz, 1H), 8.36-8.32 (m, 1H), 7.87(dd, J=8.6, 7.7 Hz, 1H), 7.81 (dd, J=5.1, 1.5 Hz, 1H), 7.73 (s, 1H),7.61-7.53 (m, 2H), 6.00 (dd, J=12.7, 4.3 Hz, 1H), 4.51-4.33 (m, 1H),4.13-3.86 (m, 2H), 3.39-3.35 (m, 2H), 2.71 (td, J=6.8, 3.1 Hz, 1H),2.43-2.25 (m, 1H), 2.13-1.97 (m, 1H), 1.68-1.40 (m, 2H), 1.03 (d, J=6.8Hz, 6H), 0.75 (br. s., 1H). MS(ESI) m/z: 638.5 [M+H]⁺. Analytical HPLC(Method A): RT=7.32 min, purity=>95.0%; Factor XIa Ki=0.34 nM, PlasmaKallikrein Ki=28 nM.

Example 91 Preparation of(9R,13S)-13-(4-{5-chloro-2-[4-(difluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(2-hydroxyethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate

(9R,13S)-13-(4-{5-Chloro-2-[4-(difluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(2-hydroxyethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate was prepared in a similar manner as the proceduresdescribed in Example 56, by using6-(5-chloro-2-(4-(difluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol(0.049 g, 0.152 mmol), prepared as described in Intermediate 16, and(9R,13S)-13-amino-3-(2-hydroxyethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(0.050 g, 0.152 mmol), prepared as described in Intermediate 40. Thecrude product was purified by prep HPLC to yield(9R,13S)-13-(4-{5-chloro-2-[4-(difluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(2-hydroxyethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate (32 mg, 27% yield) as awhite solid. ¹H NMR (400 MHz, CD₃₀D) δ 8.75 (s, 1H), 8.69 (d, J=5.1 Hz,1H), 8.56-8.50 (m, 1H), 7.87 (d, J=2.4 Hz, 1H), 7.79-7.61 (m, 4H), 7.55(s, 1H), 7.16-6.80 (m, 1H), 6.34 (d, J=0.4 Hz, 1H), 5.95 (dd, J=12.7,4.1 Hz, 1H), 4.47-4.28 (m, 2H), 4.09-3.87 (m, 2H), 2.67 (td, J=6.8, 3.0Hz, 1H), 2.34-2.19 (m, 1H), 2.09-1.91 (m, 2H), 1.65-1.34 (m, 2H), 1.00(d, J=6.8 Hz, 3H), 0.70 (br. s., 1H). MS(ESI) m/z: 636.5 [M+H]+.Analytical HPLC (Method A): RT=7.32 min, purity=>95.0%; Factor XIaKi=2.8 nM, Plasma Kallikrein Ki=220 nM.

Example 92 Preparation of(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(2-hydroxyethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate

(9R,13S)-13-{4-[5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(2-hydroxyethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate was prepared in a similar manner as the proceduresdescribed in Example 56, by using6-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol(0.042 g, 0.137 mmol), prepared as described in Intermediate 9, and(9R,13S)-13-amino-3-(2-hydroxyethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(0.045 g, 0.137 mmol), prepared as described in Intermediate 40. Thecrude product was purified by prep HPLC to yield(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(2-hydroxyethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(65 mg, 61% yield) as white solid. ¹H NMR (400 MHz, CD₃OD) δ 8.79 (s,1H), 8.73 (d, J=5.1 Hz, 1H), 8.40-8.30 (m, 1H), 7.88 (d, J=2.2 Hz, 1H),7.81 (dd, J=5.1, 1.5 Hz, 1H), 7.76-7.70 (m, 2H), 7.67-7.61 (m, 1H), 7.58(s, 1H), 6.37 (d, J=0.4 Hz, 1H), 5.96 (dd, J=12.5, 4.2 Hz, 1H),4.46-4.33 (m, 2H), 4.09-3.91 (m, 3H), 3.35 (s, 1H), 2.69 (td, J=6.8, 3.0Hz, 1H), 2.39-2.24 (m, 1H), 2.12-1.94 (m, 2H), 1.66-1.40 (m, 2H), 1.02(d, J=7.0 Hz, 3H), 0.73 (br. s., 1H). MS(ESI) m/z: 620.5 [M+H]⁺.Analytical HPLC (Method A): RT=7.29 min, purity=>95.0%; Factor XIaKi=1.3 nM, Plasma Kallikrein Ki=130 nM.

Example 93 Preparation of(9R,13S)-13-{4-[5-chloro-2-(1H-1,2,3,4-tetrazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(2-hydroxyethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate

(9R,13S)-13-{4-[5-Chloro-2-(1H-1,2,3,4-tetrazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(2-hydroxyethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate was prepared in a similar manner as the proceduresdescribed in Example 56, by using6-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)pyrimidin-4-ol (0.037 g, 0.137mmol), prepared as described in Intermediate 20, and(9R,13S)-13-amino-3-(2-hydroxyethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(0.045 g, 0.137 mmol), prepared as described in Intermediate 40. Thecrude product was purified by prep HPLC to yield(9R,13S)-13-{4-[5-chloro-2-(1H-1,2,3,4-tetrazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(2-hydroxyethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(52 mg, 52% yield) as a pale white solid. ¹H NMR (400 MHz, CD₃OD) δ 9.42(s, 1H), 8.68 (d, J=5.1 Hz, 2H), 7.88 (d, J=2.2 Hz, 1H), 7.78-7.72 (m,2H), 7.67 (d, J=8.4 Hz, 2H), 7.55 (s, 1H), 6.49 (s, 1H), 5.93 (d, J=8.8Hz, 1H), 4.45-4.29 (m, 2H), 4.08-3.88 (m, 3H), 3.32 (s, 1H), 2.66 (d,J=7.0 Hz, 1H), 2.24 (t, J=13.0 Hz, 1H), 2.08-1.88 (m, 2H), 1.65-1.49 (m,1H), 1.41 (br. s., 1H), 0.98 (d, J=6.8 Hz, 3H), 0.67 (br. s., 1H).MS(ESI) m/z: 587.5 [M+H]⁺. Analytical HPLC (Method A): RT=6.40 min,purity=>95.0%; Factor XIa Ki=0.65 nM, Plasma Kallikrein Ki=45 nM.

Example 94 Preparation of(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(2-hydroxyethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate

(9R,13S)-13-(4-{5-Chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(2-hydroxyethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate was prepared in a similar manner as the proceduresdescribed in Example 56, by using6-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}pyrimidin-4-ol(47 mg, 0.137 mmol), prepared as described in Intermediate 15, and(9R,13S)-13-amino-3-(2-hydroxyethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one (0.045 g, 0.137 mmol), prepared asdescribed in Intermediate 40. The crude product was purified by prepHPLC to yield(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(2-hydroxyethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one (67 mg, 61% yield) as a white solid. ¹HNMR (400 MHz, CD₃OD) δ 8.79 (s, 1H), 8.72 (s, 1H), 8.68-8.61 (m, 1H),7.88-7.82 (m, 1H), 7.78-7.69 (m, 2H), 7.68-7.61 (m, 2H), 7.54 (s, 1H),6.40 (s, 1H), 5.93 (dd, J=12.7, 4.1 Hz, 1H), 4.42-4.27 (m, 2H),4.03-3.86 (m, 2H), 2.65 (dt, J=6.8, 3.3 Hz, 1H), 2.33-2.15 (m, 1H),2.07-1.87 (m, 2H), 1.64-1.48 (m, 1H), 1.41 (td, J=10.0, 5.2 Hz, 1H),1.01-0.93 (m, 3H), 0.66 (br. s., 1H). MS(ESI) m/z: 654.5 [M+H]⁺.Analytical HPLC (Method A): RT=8.10 min, purity=>95.0%; Factor XIaKi=1.1 nM, Plasma Kallikrein Ki=130 nM.

Example 95 Preparation of2-[(9R,13S)-13-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-3-yl]aceticacid trifluoroacetate

A solution of(9R,13S)-13-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(2-hydroxyethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate (0.034 g, 0.053 mmol), prepared as described in Example90, in acetone (2 mL) was cooled to 0° C. To this cooled mixture wasthen added 2.86 M solution of Jones reagent (0.037 mL, 0.107 mmol) andthe resulting reaction mixture was allowed to warm to rt over a periodof 2 h. The reaction mixture was then quenched with 0.5 mL of IPA andconcentrated. The resulting residue was purified by prep HPLCpurification to afford2-[(9R,13S)-13-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-3-yl]aceticacid trifluoroacetate (8 mg, 19% yield) as a white solid. ¹H NMR (400MHz, CD₃OD) δ 8.85 (s, 1H), 8.74 (d, J=5.1 Hz, 1H), 8.34 (s, 1H), 7.87(dd, J=8.6, 7.5 Hz, 1H), 7.72 (s, 1H), 7.61-7.53 (m, 2H), 7.49 (dd,J=5.1, 1.5 Hz, 1H), 6.62 (s, 1H), 6.04 (dd, J=12.3, 4.2 Hz, 1H),5.27-5.06 (m, 2H), 2.72 (dt, J=6.7, 3.4 Hz, 1H), 2.30 (t, J=12.7 Hz,1H), 2.15-1.97 (m, 2H), 1.69-1.41 (m, 2H), 1.03 (d, J=7.0 Hz, 3H), 0.71(br. s., 1H). MS(ESI) m/z: 652.2 [M+H]⁺. Analytical HPLC (Method A):RT=7.45 min, purity=>95.0%; Factor XIa Ki=0.11 nM, Plasma KallikreinKi=12 nM.

Example 96 Preparation of2-[(9R,13S)-13-(4-{5-chloro-2-[4-(difluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-3-yl]aceticacid trifluoroacetate

2-[(9R,13S)-13-(4-{5-Chloro-2-[4-(difluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-3-yl]aceticacid was prepared in a similar manned as the procedure described inExample 95, using(9R,13S)-13-(4-{5-chloro-2-[4-(difluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(2-hydroxyethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate (0.024 g, 0.038 mmol), prepared as described in Example91, to yield2-[(9R,13S)-13-(4-{5-chloro-2-[4-(difluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-3-yl]aceticacid trifluoroacetate (6 mg, 20% yield) as a white solid. ¹H NMR (400MHz, CD₃OD) δ 8.83 (s, 1H), 8.72 (d, J=5.1 Hz, 1H), 8.56 (s, 1H), 7.91(d, J=2.4 Hz, 1H), 7.80-7.74 (m, 1H), 7.72-7.66 (m, 2H), 7.59 (s, 1H),7.49 (dd, J=5.1, 1.3 Hz, 1H), 7.19-6.86 (m, 1H), 6.38 (s, 1H), 6.03 (dd,J=12.7, 4.3 Hz, 1H), 5.27-5.06 (m, 2H), 2.72 (dt, J=6.6, 3.3 Hz, 1H),2.34-2.22 (m, 1H), 2.13-1.94 (m, 2H), 1.68-1.40 (m, 2H), 1.03 (d, J=7.0Hz, 3H), 0.71 (br. s., 1H). MS(ESI) m/z: 650.3 [M+H]⁺. Analytical HPLC(Method A): RT=7.52 min, purity=>95.0%; Factor XIa Ki=0.65 nM, PlasmaKallikrein Ki=78 nM.

Example 97 Preparation of2-[(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-3-yl]aceticacid trifluoroacetate

2-[(9R,13S)-13-{4-[5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-3-yl]aceticacid trifluoroacetate was prepared in a similar manned as the proceduredescribed in Example 95, using(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(2-hydroxyethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate (0.038 g, 0.061 mmol), prepared as described in Example92, to yield2-[(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-3-yl]aceticacid trifluoroacetate (8 mg, 17% yield) as a white solid. ¹H NMR (400MHz, CD₃OD) δ 8.85 (s, 1H), 8.73 (d, J=5.1 Hz, 1H), 8.36 (s, 1H),7.92-7.88 (m, 1H), 7.79-7.64 (m, 3H), 7.59 (s, 1H), 7.49 (dd, J=5.1, 1.3Hz, 1H), 6.38 (s, 1H), 6.03 (dd, J=12.5, 4.0 Hz, 1H), 5.27-5.04 (m, 2H),2.72 (m, 1H), 2.30 (m, 1H), 2.14-1.97 (m, 2H), 1.69-1.42 (m, 2H), 1.03(d, J=6.8 Hz, 3H), 0.71 (br. s., 1H). MS(ESI) m/z: 634.3 [M+H]+.Analytical HPLC (Method A): RT=7.49 min, purity=>95.0%; Factor XIaKi=0.38 nM, Plasma Kallikrein Ki=52 nM.

Example 98 Preparation of2-[(9R,13S)-13-{4-[5-chloro-2-(1H-1,2,3,4-tetrazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-3-yl]aceticacid trifluoroacetate

2-[(9R,13S)-13-{4-[5-Chloro-2-(1H-1,2,3,4-tetrazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-3-yl]aceticacid trifluoroacetate was prepared in a similar manned as the proceduredescribed in Example 95, using(9R,13S)-13-{4-[5-chloro-2-(1H-1,2,3,4-tetrazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(2-hydroxyethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate (0.020 g, 0.034 mmol), prepared as described in Example93, to yield2-[(9R,13S)-13-{4-[5-chloro-2-(1H-1,2,3,4-tetrazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-3-yl]aceticacid trifluoroacetate (5.1 mg, 20% yield) as a white solid. ¹H NMR (400MHz, CD₃OD) δ 9.45 (s, 1H), 8.80-8.68 (m, 2H), 7.95-7.90 (m, 1H),7.83-7.76 (m, 1H), 7.74-7.67 (m, 2H), 7.59 (s, 1H), 7.49 (dd, J=5.1, 1.3Hz, 1H), 6.53 (s, 1H), 6.01 (dd, J=12.5, 4.0 Hz, 1H), 5.28-5.05 (m, 2H),2.71 (m, 1H), 2.27 (m, 1H), 2.13-1.95 (m, 2H), 1.66-1.39 (m, 2H), 1.03(d, J=7.0 Hz, 3H), 0.72 (br. s., 1H). MS(ESI) m/z: 601.3 [M+H]⁺.Analytical HPLC (Method A): RT=6.62 min, purity=>95.0%; Factor XIaKi=0.16 nM, Plasma Kallikrein Ki=20 nM.

Example 99 Preparation of2-[(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-3-yl]aceticacid trifluoroacetate

2-[(9R,13S)-13-(4-{5-Chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-3-yl]aceticacid trifluoroacetate was prepared in a similar manned as the proceduredescribed in Example 95, using(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(2-hydroxyethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate (0.038 g, 0.058 mmol), prepared as described in Example94, to yield2-[(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-3-yl]aceticacid trifluoroacetate (7.5 mg, 16% yield) as a white solid. ¹H NMR (400MHz, CD₃OD) δ 8.84 (s, 1H), 8.80 (s, 1H), 8.73-8.68 (m, 1H), 7.92 (d,J=2.4 Hz, 1H), 7.80-7.75 (m, 1H), 7.71 (m, 2H), 7.58 (s, 1H), 7.49 (dd,J=5.1, 1.3 Hz, 1H), 6.46 (s, 1H), 6.03 (dd, J=12.4, 4.1 Hz, 1H),5.26-5.06 (m, 2H), 2.77-2.66 (m, 1H), 2.27 (m, 1H), 2.13-1.94 (m, 2H),1.67-1.40 (m, 2H), 1.02 (d, J=6.8 Hz, 3H), 0.71 (br. s., 1H). MS(ESI)m/z: 668.3 [M+H]+; Factor XIa Ki=0.29 nM, Plasma Kallikrein Ki=52 nM.

Example 100 Preparation of(9R,13S)-13-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate

100A. Preparation of(9R,13S)-13-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-3-{[2-(trimethylsilyl)ethoxy]methyl}-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

(9R,13S)-13-{4-[3-Chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-3-{[2-(trimethylsilyl)ethoxy]methyl}-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onewas prepared in a similar manner as the procedures described in Example56, by using6-(3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl)pyrimidin-4-ol(0.027 g, 0.083 mmol), prepared as described in Intermediate 10, andbenzylN-[(9R,13S)-9-methyl-8-oxo-3-{[2-(trimethylsilyl)ethoxy]methyl}-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate(0.034 g, 0.081 mmol), prepared as described in Intermediate 41, toyield(9R,13S)-13-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-3-{[2-(trimethylsilyl)ethoxy]methyl}-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(10 mg, 14% yield) as pale white solid. MS(ESI) m/z: 723.5 [M+H]⁺.

100B. Preparation of(9R,13S)-13-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate

To a solution of(9R,13S)-13-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-3-{[2-(trimethylsilyl)ethoxy]methyl}-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(10 mg, 0.014 mmol), in DCM (0.8 mL) was added TFA (0.2 mL, 2.60 mmol)and the resulting solution was stirred at rt for 30 min. The reactionmixture was then concentrated and the residue was purified by prep HPLCpurification to give(9R,13S)-13-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate (4.8 mg, 46% yield) asa pale pink solid. ¹H NMR (400 MHz, CD₃OD) δ 8.74-8.59 (m, 2H),8.42-8.30 (m, 1H), 7.99 (s, 1H), 7.88 (dd, J=8.6, 7.7 Hz, 1H), 7.77 (s,1H), 7.67 (dd, J=5.3, 1.3 Hz, 1H), 7.58 (dd, J=8.6, 1.5 Hz, 1H), 6.65(s, 1H), 6.07 (d, J=8.4 Hz, 1H), 2.90-2.74 (m, 1H), 2.44-2.18 (m, 2H),2.14-2.02 (m, 1H), 1.83-1.67 (m, 1H), 1.63-1.47 (m, 1H), 1.11 (d, J=6.8Hz, 3H), 1.00 (br. s., 1H). MS(ESI) m/z: 594.5 [M+H]⁺. Analytical HPLC(Method A): RT=7.11 min, purity=>95.0%; Factor XIa Ki=1.6 nM, PlasmaKallikrein Ki=85 nM.

Example 101 Preparation of(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate

101A. Preparation of(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-3-{[2-(trimethylsilyl)ethoxy]methyl}-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

(9R,13S)-13-{4-[5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-3-{[2-(trimethylsilyl)ethoxy]methyl}-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onewas prepared in a similar manner as the procedure described in Example56, by using6-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol(0.034 g, 0.110 mmol), prepared as described in Intermediate 9, andbenzylN-[(9R,13S)-9-methyl-8-oxo-3-{[2-(trimethylsilyl)ethoxy]methyl}-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate(0.046 g, 0.110 mmol), prepared as described in Intermediate 41, to give(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-3-{[2-(trimethylsilyl)ethoxy]methyl}-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(12 mg, 14% yield) as pale yellow solid. MS(ESI) m/z: 706.5 [M+H]⁺.

101B. Preparation of(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate

To a solution of(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-3-{[2-(trimethylsilyl)ethoxy]methyl}-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(12 mg, 0.017 mmol) in DCM (0.8 mL) was added TFA (0.2 mL, 2.60 mmol)and the reaction was stirred at rt for 30 min. The reaction mixture wasthen concentrated and the residue was purified by prep HPLC purificationto give(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate (5.3 mg, 43% yield) as a pale pink solid. ¹H NMR (400MHz, CD₃OD) δ 8.72-8.57 (m, 2H), 8.37 (s, 1H), 7.99 (s, 1H), 7.91 (d,J=2.2 Hz, 1H), 7.82-7.72 (m, 2H), 7.70-7.63 (m, 2H), 6.41 (s, 1H),6.11-5.95 (m, 1H), 2.81 (td, J=6.8, 3.4 Hz, 1H), 2.44-2.17 (m, 2H),2.15-2.01 (m, 1H), 1.80-1.65 (m, 1H), 1.62-1.46 (m, 1H), 1.11 (d, J=7.0Hz, 3H), 1.01 (br. s., 1H). MS(ESI) m/z: 576.4 [M+H]⁺. Analytical HPLC(Method A): RT=6.98 min, purity=>95.0%; Factor XIa Ki=4.2 nM, PlasmaKallikrein Ki=300 nM.

Example 102 Preparation of methyl(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-8-oxo-2,3,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),3,5,14,16-pentaene-4-carboxylatetrifluoroacetate

102A. Preparation of (S)-tert-butyl(1-(4-hydrazinylpyridin-2-yl)but-3-en-1-yl) carbamate

A vial with a Teflon septum cap was charged with a solution of(S)-tert-butyl (1-(4-chloropyridin-2-yl)but-3-en-1-yl)carbamate (2 g,7.0 mmol), prepared as described in Intermediate 23, and 35% aqhydrazine (10 mL, 111 mmol, 15.75 equiv) in EtOH (10 mL). The solutionwas heated by an aluminum block at 115° C. for 18 h. The reaction wasconcentrated to give a pink oil. The residue was purified by normalphase silica gel chromatography to give (S)-tert-butyl(1-(4-hydrazinylpyridin-2-yl)but-3-en-1-yl)carbamate (1.67 g, 85% yield)as a yellow, foam. ¹H NMR (400 MHz, CDCl₃) δ 8.22 (d, J=5.7 Hz, 1H),6.60 (s, 1H), 6.57 (dd, J=5.5, 2.4 Hz, 1H), 5.79-5.54 (m, 3H), 5.14-4.99(m, 2H), 4.74-4.62 (m, 1H), 2.59 (t, J=6.7 Hz, 2H), 1.52-1.40 (m, 9H).MS(ESI) m/z: 279.2 (M+H)⁺.

102B. Preparation of (S)-ethyl5-amino-1-(2-(1-((tert-butoxycarbonyl)amino)but-3-en-1-yl)pyridin-4-yl)-1H-pyrazole-3-carboxylate

Sodium (Z)-1-cyano-3-ethoxy-3-oxoprop-1-en-2-olate (0.29 g, 1.8 mmol)was suspended in a solution of (S)-tert-butyl(1-(4-hydrazinylpyridin-2-yl)but-3-en-1-yl) carbamate (0.50 g, 1.8 mmol)in EtOH (15 ml). TFA (0.4 ml, 5.39 mmol, 3 equiv) was added dropwise andthe solid slowly dissolved upon heating to 80° C. Stirring was continuedat 80° C. for 2 h, then the reaction was cooled to rt. The reaction wasconcentrated to an oil and the residue dissolved in EtOAc. The organiclayer was washed with pH=7 phosphate buffer, separated and the organiclayer was concentrated to yield an oil. Purification of the crude oil bynormal phase silica gel chromatography yielded (S)-ethyl5-amino-1-(2-(1-((tert-butoxycarbonyl)amino)but-3-en-1-yl)pyridin-4-yl)-1H-pyrazole-3-carboxylate(0.7 g, 97% yield) as a clear, colorless, thick oil. ¹H NMR (400 MHz,CDCl₃) δ 8.71-8.67 (m, 1H), 7.64 (d, J=2.0 Hz, 1H), 7.60 (dd, J=5.4, 2.1Hz, 1H), 6.20 (s, 1H), 5.79-5.66 (m, 1H), 5.56-5.42 (m, 1H), 5.15-5.06(m, 3H), 4.93-4.82 (m, 1H), 4.44 (q, J=7.1 Hz, 2H), 4.03 (br. s., 2H),2.66 (m, 2H), 1.46 (s, 9H), 1.45-1.41 (t, J=7.1 Hz, 3H). MS(ESI) m/z:402.2 (M+H)⁺.

102C. Preparation of ethyl1-(2-((S)-1-((tert-butoxycarbonyl)amino)but-3-en-1-yl)pyridin-4-yl)-5-((R)-2-methylbut-3-enamido)-1H-pyrazole-3-carboxylate

To a N₂ flushed, 3-necked, 250 mL RBF was added a solution (S)-ethyl5-amino-1-(2-(1-((tert-butoxycarbonyl)amino)but-3-en-1-yl)pyridin-4-yl)-1H-pyrazole-3-carboxylate(1.75 g, 4.36 mmol) and EtOAc (15 mL). The solution was cooled to −10°C. and (R)-2-methylbut-3-enoic acid (436 mg, 4.36 mmol), as prepared inIntermediate 2, pyridine (0.705 mL, 8.72 mmol) and T3P® (3.89 mL, 6.54mmol) were added. The cooling bath was removed and the solution wasallowed to warm to rt and then stir for 20 h. Water (20 mL) and EtOAc(20 mL) were added and the mixture was stirred for 30 min. The organicphase was separated and the aqueous layer was extracted with EtOAc (20mL). The combined organic extracts were washed with brine (15 mL), driedover Na₂SO₄, filtered and concentrated. Purification by normal phasechromatography eluting with a gradient of DCM/MeOH gave ethyl1-(2-((S)-1-((tert-butoxycarbonyl)amino)but-3-en-1-yl)pyridin-4-yl)-5-((R)-2-methylbut-3-enamido)-1H-pyrazole-3-carboxylate(1.81 g, 86% yield) as a white foaming solid. MS(ESI) m/z: 484.5 [M+H]⁺.

102D. Preparation of ethyl(10E,13S)-13-{[(tert-butoxy)carbonyl]amino}-9-methyl-8-oxo-2,3,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),3,5,10,14,16-hexaene-4-carboxylate

To a N₂ flushed, 250 mL, 3-necked, RBF was added a solution of ethyl1-(2-((S)-1-((tert-butoxycarbonyl)amino)but-3-en-1-yl)pyridin-4-yl)-5-((R)-2-methylbut-3-enamido)-1H-pyrazole-3-carboxylate(1.81 g, 3.74 mmol) and CH₃SO₃H (0.23 ml, 3.56 mmol) in DCM (30 mL). Theresulting solution heated to 40° C. The solution was sparged with Ar for15 min. Second Generation Grubbs Catalyst (253 mg, 0.298 mmol) dissolvedin DCM (10 mL) was added dropwise over a period of 10 min at 40° C. Thereaction mixture was heated at 40° C. for overnight. After cooling tort, the solvent was removed and the residue was purified by normal phasechromatography eluting with a gradient of DCM/MeOH to yield ethyl(10E,13S)-13-{[(tert-butoxy)carbonyl]amino}-9-methyl-8-oxo-2,3,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),3,5,10,14,16-hexaene-4-carboxylate(670 mg, 39% yield) as a gray solid. MS(ESI) m/z: 556.5 [M+H]⁺.

102E. Preparation of ethyl(13S)-13-{[(tert-butoxy)carbonyl]amino}-9-methyl-8-oxo-2,3,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),3,5,14,16-pentaene-4-carboxylate

Pd/C (0.16 g, 0.147 mmol) was added to a 250 mL Parr hydrogenation flaskcontaining a solution of ethyl(10E,13S)-13-{[(tert-butoxy)carbonyl]amino}-9-methyl-8-oxo-2,3,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),3,5,10,14,16-hexaene-4-carboxylate(670 mg, 1.471 mmol) in EtOH (15 mL). The flask was purged with N₂ andpressurized to 55 psi of H₂ and allowed to stir overnight. The reactionwas filtered through a pad of CELITE® and concentrated to yield ethyl(13S)-13-{[(tert-butoxy)carbonyl]amino}-9-methyl-8-oxo-2,3,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),3,5,14,16-pentaene-4-carboxylate(500 mg, 70% yield) as a tan solid. MS(ESI) m/z: 458.4 [M+H]⁺.

102F. Ethyl(9R,13S)-13-amino-9-methyl-8-oxo-2,3,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),3,5,14,16-pentaene-4-carboxylate,bis hydrochloride

To a solution of ethyl(13S)-13-{[(tert-butoxy)carbonyl]amino}-9-methyl-8-oxo-2,3,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),3,5,14,16-pentaene-4-carboxylate(500 mg, 1.093 mmol) in MeOH (5 mL) was added 4 M HCl in dioxane (5 mL,20.0 mmol) and the resulting solution was stirred at rt for 1 h. Thereaction mixture was then concentrated to give ethyl(9R,13S)-13-amino-9-methyl-8-oxo-2,3,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),3,5,14,16-pentaene-4-carboxylate,bis hydrochloride (380 mg, 97% yield, mixture of methyl and ethylesters) as a pale yellow solid. Additionally, also observed was theformation of methyl(9R,13S)-13-amino-9-methyl-8-oxo-2,3,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),3,5,14,16-pentaene-4-carboxylate,bis hydrochloride due to transesterification of the ethyl ester tomethyl ester as MeOH was used as solvent. The mixture of ethyl(9R,13S)-13-amino-9-methyl-8-oxo-2,3,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),3,5,14,16-pentaene-4-carboxylate,bis hydrochloride and methyl(9R,13S)-13-amino-9-methyl-8-oxo-2,3,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),3,5,14,16-pentaene-4-carboxylate,bis hydrochloride were dissolved in MeOH (4 mL) to give a clear, palebrown solution. The solution was added to a pre-rinsed AGILENT®StratoSpheres SPE PL-HCO₃ MP Resin cartridge. Gravity filtration,eluting with MeOH, gave a clear, slightly yellow filtrate. Concentrationprovided ethyl(9R,13S)-13-amino-9-methyl-8-oxo-2,3,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),3,5,14,16-pentaene-4-carboxylate(MS(ESI) m/z: 330.5 [M+H]+) and methyl(9R,13S)-13-amino-9-methyl-8-oxo-2,3,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),3,5,14,16-pentaene-4-carboxylate(295 mg, 97%) carboxylate (MS(ESI) m/z: 344.3 [M+H]⁺) mixture as a palebrown solid.

102G. Preparation of methyl(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-8-oxo-2,3,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),3,5,14,16-pentaene-4-carboxylatetrifluoroacetate

Methyl(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl}phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl)-9-methyl-8-oxo-2,3,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),3,5,14,16-pentaene-4-carboxylatetrifluoroacetate was prepared in a similar manner as the proceduredescribed in Example 56, using6-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol(0.035 g, 0.115 mmol), prepared as described in Intermediate 9, and themixture of ethyl(9R,13S)-13-amino-9-methyl-8-oxo-2,3,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),3,5,14,16-pentaene-4-carboxylateand methyl(9R,13S)-13-amino-9-methyl-8-oxo-2,3,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),3,5,14,16-pentaene-4-carboxylate(0.041 g, 0.115 mmol) to yield a mixture of methyl(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-8-oxo-2,3,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),3,5,14,16-pentaene-4-carboxylateand ethyl(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-8-oxo-2,3,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),3,5,14,16-pentaene-4-carboxylatewhich were further purified by prep HPLC to yield the desired methyl(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-8-oxo-2,3,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),3,5,14,16-pentaene-4-carboxylatetrifluoroacetate (7 mg, 8% yield) as white solid. ¹H NMR (400 MHz,CD₃OD) δ 8.95 (s, 1H), 8.74 (d, J=5.3 Hz, 1H), 8.34 (s, 1H), 7.89 (d,J=2.2 Hz, 1H), 7.82 (d, J=1.8 Hz, 1H), 7.77-7.70 (m, 1H), 7.68-7.58 (m,2H), 6.84 (s, 1H), 6.37 (s, 1H), 6.12 (dd, J=12.4, 5.0 Hz, 1H), 3.94 (s,3H), 2.84 (br. s., 1H), 2.34-2.12 (m, 2H), 2.08-1.92 (m, 1H), 1.80-1.48(m, 2H), 0.98 (d, J=6.8 Hz, 3H), 0.45 (br. s., 1H). MS(ESI) m/z: 634.3[M+H]⁺. Analytical HPLC (Method A): RT=9.07 min, purity=>95.0%; FactorXIa Ki=11 nM, Plasma Kallikrein Ki=360 nM.

Example 103 Preparation of methyl(9R,13S)-13-(4-{5-chloro-2-[4-(difluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-9-methyl-8-oxo-2,3,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),3,5,14,16-pentaene-4-carboxylatetrifluoroacetate

Methyl(9R,13S)-13-(4-{5-chloro-2-[4-(difluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-9-methyl-8-oxo-2,3,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),3,5,14,16-pentaene-4-carboxylatetrifluoroacetate was prepared in a similar manner as the proceduredescribed in Example 56, by using6-(5-chloro-2-(4-(difluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol(0.037 g, 0.115 mmol), prepared as described in Intermediate 16, and themixture of ethyl(9R,13S)-13-amino-9-methyl-8-oxo-2,3,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),3,5,14,16-pentaene-4-carboxylateand methyl(9R,13S)-13-amino-9-methyl-8-oxo-2,3,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),3,5,14,16-pentaene-4-carboxylate(0.041 g, 0.115 mmol), prepared as described in Example 102F, to yield amixture of methyl(9R,13S)-13-(4-{5-chloro-2-[4-(difluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-9-methyl-8-oxo-2,3,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),3,5,14,16-pentaene-4-carboxylateand ethyl(9R,13S)-13-(4-{5-chloro-2-[4-(difluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-9-methyl-8-oxo-2,3,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),3,5,14,16-pentaene-4-carboxylatewhich was further purified by prep HPLC to yield methyl(9R,13S)-13-(4-{5-chloro-2-[4-(difluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-9-methyl-8-oxo-2,3,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),3,5,14,16-pentaene-4-carboxylate trifluoroacetate (7 mg, 8% yield)as white solid. ¹H NMR (400 MHz, CD₃OD) δ 8.95 (s, 1H), 8.75 (d, J=5.3Hz, 1H), 8.59-8.55 (m, 1H), 7.93 (d, J=2.4 Hz, 1H), 7.84 (d, J=2.0 Hz,1H), 7.80-7.74 (m, 1H), 7.73-7.68 (m, 1H), 7.64 (dd, J=5.5, 2.0 Hz, 1H),7.19-6.88 (m, 1H), 6.86 (s, 1H), 6.39 (s, 1H), 6.14 (dd, J=12.5, 5.1 Hz,1H), 3.97 (s, 3H), 2.85 (d, J=6.8 Hz, 1H), 2.36-2.13 (m, 2H), 2.08-1.92(m, 1H), 1.77-1.51 (m, 2H), 1.01 (d, J=6.8 Hz, 3H), 0.45 (d, J=13.6 Hz,1H). MS(ESI) m/z: 650.3 [M+H]⁺. Analytical HPLC (Method A): RT=8.98 min,purity=>95.0%; Factor XIa Ki=6.5 nM, Plasma Kallikrein Ki=200 nM.

Example 104 Preparation of(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-8-oxo-2,3,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),3,5,14,16-pentaene-4-carboxylicacid trifluoroacetate

Ethyl(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-8-oxo-2,3,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),3,5,14,16-pentaene-4-carboxylate(0.035 g, 0.054 mmol), prepared as described in Example 102, washydrolyzed using 2 M LiOH solution (0.08 mL, 0.162 mmol) at rt for 1 h.The reaction was neutralized using 1 N HCl and concentrated. The crudeproduct was purified using prep HPLC to yield(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-8-oxo-2,3,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),3,5,14,16-pentaene-4-carboxylicacid trifluoroacetate (20 mg, 48% yield) as a white solid. ¹H NMR (400MHz, CD₃OD) δ 8.98 (s, 1H), 8.76 (d, J=5.3 Hz, 1H), 8.36 (s, 1H), 7.92(d, J=2.2 Hz, 1H), 7.85 (d, J=2.0 Hz, 1H), 7.79-7.73 (m, 1H), 7.70-7.63(m, 2H), 6.85 (s, 1H), 6.40 (d, J=0.7 Hz, 1H), 6.15 (dd, J=12.4, 5.0 Hz,1H), 2.88 (d, J=8.8 Hz, 1H), 2.38-2.15 (m, 2H), 2.10-1.94 (m, 1H),1.80-1.52 (m, 2H), 1.01 (d, J=6.8 Hz, 3H), 0.48 (br. s., 1H). MS(ESI)m/z: 620.3 [M+H]⁺. Analytical HPLC (Method A): RT=7.96 min,purity=>95.0%; Factor XIa Ki=1.7 nM, Plasma Kallikrein Ki=470 nM.

Example 105 Preparation of(9R,13S)-13-(4-{5-chloro-2-[4-(difluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-9-methyl-8-oxo-2,3,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),3,5,14,16-pentaene-4-carboxylicacid trifluoroacetate

Ethyl(9R,13S)-13-(4-{5-chloro-2-[4-(difluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-9-methyl-8-oxo-2,3,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),3,5,14,16-pentaene-4-carboxylate(0.035 g, 0.053 mmol), prepared as described in Example 103, washydrolyzed using 2 M LiOH (0.079 mL, 0.158 mmol) at rt for 1 h. Thereaction was neutralized using 1 N HCl and concentrated. The crudeproduct was purified using prep HPLC purification to yield(9R,13S)-13-(4-{5-chloro-2-[4-(difluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-9-methyl-8-oxo-2,3,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),3,5,14,16-pentaene-4-carboxylicacid trifluoroacetate (10 mg, 24% yield) as a white solid. ¹H NMR (400MHz, CD₃OD) δ 8.96 (s, 1H), 8.75 (d, J=5.3 Hz, 1H), 8.60-8.55 (m, 1H),7.93 (d, J=2.2 Hz, 1H), 7.85 (d, J=1.8 Hz, 1H), 7.80-7.74 (m, 1H),7.73-7.62 (m, 2H), 7.20-6.89 (m, 1H), 6.85 (s, 1H), 6.39 (s, 1H), 6.15(dd, J=12.5, 4.8 Hz, 1H), 2.93-2.82 (m, 1H), 2.34-2.14 (m, 2H),2.09-1.95 (m, 1H), 1.77-1.52 (m, 2H), 1.01 (d, J=6.8 Hz, 3H), 0.46 (d,J=10.1 Hz, 1H). MS(ESI) m/z: 636.3 [M+H]⁺. Analytical HPLC (Method A):RT=7.97 min, purity=>95.0%; Factor XIa Ki=0.92 nM, Plasma KallikreinKi=470 nM.

Example 106 Preparation of(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(²H₃)methyl-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate

To a vial (4 ml) containing a suspension6-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol(0.028 g, 0.089 mmol), prepared as described in Intermediate 9, in ACN(1 ml) was added HATU (0.044 g, 0.116 mmol) and DBU (0.020 ml, 0.134mmol). After 20 min,(9R,13S)-13-amino-3-(²H₃)methyl-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(0.027 g, 0.089 mmol), prepared as described in Intermediate 33, in DMF(1.0 ml) was added at rt. After 4 h, the crude mixture was purified byreverse phase chromatography (PHENOMENEX® Luna Axia C18 5μ30×100 mmcolumn, Solvent A: 20% ACN—80% H₂O— 0.1% TFA; Solvent B: 80% ACN—20%H₂O— 0.1% TFA) to give(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(²H₃)methyl-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate (19 mg, 28.6%) as awhite solid. MS(ESI) m/z: 593.1 (M+H)⁺. ¹H NMR (500 MHz, CD₃OD) δ 8.84(s, 1H), 8.75 (d, J=5.0 Hz, 1H), 8.36 (s, 1H), 7.91 (d, J=2.5 Hz, 1H),7.76 (dd, J=8.5, 2.2 Hz, 1H), 7.71 (s, 1H), 7.67 (d, J=8.5 Hz, 1H),7.56-7.50 (m, 2H), 6.39 (s, 1H), 6.01 (dd, J=12.5, 4.0 Hz, 1H), 2.73(td, J=6.6, 3.0 Hz, 1H), 2.32 (ddt, J=12.8, 8.6, 4.4 Hz, 1H), 2.13-1.99(m, 2H), 1.67-1.59 (m, 1H), 1.53-1.45 (m, 1H), 1.03 (d, J=6.9 Hz, 3H),0.71 (br. s., 1H). Analytical HPLC (Method A): RT=8.55 min,purity=99.0%; Factor XIa Ki=0.27 nM, Plasma Kallikrein Ki=27 nM.

Example 107 Preparation of(9R,13S)-13-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(²H₃)methyl-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate

To a vial (4 ml) containing a suspension6-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]pyrimidin-4-olhydrobromide (0.034 g, 0.083 mmol), prepared as described inIntermediate 10, in ACN (1 ml) was added HATU (0.041 g, 0.107 mmol) andDBU (0.034 ml, 0.223 mmol). After 30 min,(9R,13S)-13-amino-3-(²H₃)methyl-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(0.027 g, 0.089 mmol), prepared as described in Intermediate 33, in DMF(1.0 ml) was added at rt. After 2 h, the crude mixture was purified byreverse phase chromatography (PHENOMENEX® Luna Axia C18 5μ 30×100 mmcolumn, Solvent A: 20% ACN—80% H₂O— 0.1% TFA; Solvent B: 80% ACN—20%H₂O— 0.1% TFA) to give(9R,13S)-13-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(²H₃)methyl-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate (20.3 mg, 32.2%) as a white solid. MS(ESI) m/z: 611.2(M+H)⁺ and 613.1 (M+2+H)⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.85 (s, 1H), 8.78(d, J=5.1 Hz, 1H), 8.36 (s, 1H), 7.93-7.87 (m, 1H), 7.75 (s, 1H),7.60-7.55 (m, 2H), 7.53 (s, 1H), 6.64 (s, 1H), 6.03 (dd, J=12.7, 4.1 Hz,1H), 2.74 (td, J=6.6, 3.1 Hz, 1H), 2.38-2.29 (m, 1H), 2.14-2.01 (m, 2H),1.69-1.61 (m, 1H), 1.54-1.46 (m, 1H), 1.05 (d, J=7.0 Hz, 3H), 0.78-0.70(m, 1H). Analytical HPLC (Method A): RT=8.66 min, purity=96.8%; FactorXIa Ki=0.1 nM, Plasma Kallikrein Ki=8 nM.

Example 108 Preparation of(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

To a vial (4 ml) containing a suspension6-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol(0.023 g, 0.075 mmol), prepared as described in Intermediate 9, in ACN(1 ml) was added HATU (0.037 g, 0.097 mmol) and DBU (0.017 ml, 0.112mmol). After 30 min,(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(0.025 g, 0.075 mmol), prepared as described in Intermediate 35, in DMF(1.0 ml) was added at rt. After stirring overnight, the crude mixturewas concentrated and the residue purified by reverse phasechromatography (PHENOMENEX® Luna Axia C18 5μ 30×100 mm column, SolventA: 20% ACN—80% H₂O— 0.1% TFA; Solvent B: 80% ACN—20% H₂O— 0.1% TFA) togive(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(11 mg, 22.4%) as a white solid. MS(ESI) m/z: 625.1 (M+H)⁺. ¹H NMR (400MHz, CD₃OD) δ 8.84 (s, 1H), 8.75 (d, J=5.0 Hz, 1H), 8.36 (s, 1H), 7.91(d, J=2.5 Hz, 1H), 7.76 (dd, J=8.5, 2.2 Hz, 1H), 7.71 (s, 1H), 7.67 (d,J=8.5 Hz, 1H), 7.56-7.50 (m, 2H), 6.39 (s, 1H), 6.01 (dd, J=12.5, 4.0Hz, 1H), 2.73 (td, J=6.6, 3.0 Hz, 1H), 2.32 (ddt, J=12.8, 8.6, 4.4 Hz,1H), 2.13-1.99 (m, 2H), 1.67-1.59 (m, 1H), 1.53-1.45 (m, 1H), 1.03 (d,J=6.9 Hz, 3H), 0.71 (br. s., 1H). Analytical HPLC (Method A): RT=10.12min, purity=98.0%; Factor XIa Ki=0.1 nM, Plasma Kallikrein Ki=16 nM.

Example 109 Preparation of(9R,13S)-13-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

To a vial (4 ml) containing a suspension6-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]pyrimidin-4-ol(0.020 g, 0.060 mmol), prepared as described in Intermediate 10, in ACN(1 ml) was added HATU (0.030 g, 0.107 mmol) and DBU (0.014 ml, 0.090mmol). After 30 min,(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(0.020 g, 0.060 mmol), prepared as described in Intermediate 35, in DMF(1.0 ml) was added at rt. After 2 h, the crude mixture was purified byreverse phase chromatography (PHENOMENEX® Luna Axia C18 5μ 30×100 mmcolumn, Solvent A: 20% ACN—80% H₂O— 0.1% TFA; Solvent B: 80% ACN—20%H₂O— 0.1% TFA) to give(9R,13S)-13-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(7.5 mg, 19.1%) as a white solid. MS(ESI) m/z: 643.1 (M+H)⁺. ¹H NMR (400MHz, CD₃OD) δ 8.33 (s, 1H), 8.26 (s, 1H), 7.91-7.77 (m, 3H), 7.67-7.49(m, 4H), 7.41 (d, J=7.7 Hz, 1H), 6.66 (s, 1H), 5.85 (dd, J=12.9, 3.2 Hz,1H), 2.53 (td, J=6.8, 3.2 Hz, 1H), 2.43-2.34 (m, 1H), 2.21-2.10 (m, 1H),1.98-1.88 (m, 1H), 1.65-1.53 (m, 2H), 1.29-1.15 (m, 4H). Analytical HPLC(Method A): RT=10.18 min, purity=98.5%; Factor XIa Ki=0.1 nM, PlasmaKallikrein Ki=5 nM.

Example 110 Preparation of(9R,13S)-13-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl(10,11-²H₂)-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate

110A. Preparation of tert-butylN-[(9R,13S)-3,9-dimethyl-8-oxo(10,11-²H₂)-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate

To a solution of tert-butylN-[(9R,10E,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate(165 mg, 0.415 mmol), prepared as described in Intermediate 32E, inCD₃OD (7 ml), under N₂ was added Pd/C (44.2 mg, 0.042 mmol), and theresulting solution was purged and refilled with N₂, then purged andrefilled with D2 (3×). The solution was stirred at rt at 50 psi D2 for29 h. The reaction mixture was filtered through CELITE® followed by asyringe filter. The filtrate was concentrated to dryness and driedfurther under vacuum to give tert-butylN-[(9R,13S)-3,9-dimethyl-8-oxo(10,11-²H₂)-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamateas a light brown solid. MS(ESI) m/z: 402.3 (M+H)⁺. ¹H NMR (400 MHz,CD₃OD) δ 8.68 (d, J=5.3 Hz, 1H), 7.49-7.43 (m, 3H), 4.77 (dd, J=11.0,5.3 Hz, 1H), 4.05 (s, 3H), 2.75-2.65 (m, 1H), 1.94 (br. s., 1H),1.90-1.80 (m, 1H), 1.73-1.61 (m, 1H), 1.54 (t, J=5.8 Hz, 1H), 1.42 (s,9H), 0.94 (d, J=6.8 Hz, 3H).

110B. Preparation of(9R,13S)-13-amino-3,9-dimethyl(10,11-²H₂)-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

CF₃COOD (0.230 ml, 2.99 mmol) was added to a solution of tert-butylN-[(9R,13S)-3,9-dimethyl-8-oxo(10,11-²H₂)-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate(0.040 g, 0.100 mmol) in CD₂Cl₂ (1 ml, 15.67 mmol) at rt. After 1 h, thereaction mixture was concentrated. The residue was dissolved in MeOH andfree based by passing through two consecutive resin bound NaHCO₃cartridges (StratoSpheres SPE; 500 mg, 0.90 mmol loading) andconcentrated.(9R,13S)-13-Amino-3,9-dimethyl(10,11-²H₂)-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one,was carried forward ‘as is’ to next reaction. MS(ESI) m/z: 302.2 (M+H)⁺.

110C. Preparation of(9R,13S)-13-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl(10,11-²H₂)-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate

To a vial (4 ml) containing a suspension6-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]pyrimidin-4-ol(0.027 g, 0.083 mmol), prepared as described in Intermediate 10, in ACN(1 ml) was added HATU (0.041 g, 0.108 mmol) and DBU (0.019 ml, 0.124mmol). After 30 min,(9R,13S)-13-amino-3,9-dimethyl(10,11-²H₂)-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one,in DMF (1.0 ml) was added at rt. After 2 h, the crude mixture waspurified by reverse phase chromatography (PHENOMENEX® Luna Axia C185μ30×100 mm column, Solvent A: 20% ACN—80% H₂O— 0.1% TFA; Solvent B: 80%ACN—20% H₂O— 0.1% TFA) to give(9R,13S)-13-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl(10,11-²H₂)-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate (22 mg, 35.9%) as a white solid. MS(ESI) m/z: 610.2(M+H)⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.84 (s, 1H), 8.77 (d, J=5.1 Hz, 1H),8.35 (s, 1H), 7.88 (dd, J=8.7, 7.6 Hz, 1H), 7.74 (s, 1H), 7.61-7.54 (m,2H), 7.52 (s, 1H), 6.63 (s, 1H), 6.02 (dd, J=12.8, 4.0 Hz, 1H), 4.08 (s,3H), 2.72 (t, J=6.8 Hz, 1H), 2.36-2.29 (m, 1H), 2.07-2.00 (m, 1H), 1.61(t, J=6.3 Hz, 1H), 1.47 (d, J=3.7 Hz, 1H), 1.03 (d, J=6.8 Hz, 3H).Analytical HPLC (Method A): RT=7.94 min, purity=99.3%; Factor XIa Ki=0.1nM, Plasma Kallikrein Ki=8 nM.

Example 111 Preparation of(9R,13S)-13-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(²H₃)methyl-9-methyl(10,11-²H₂)-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate

111A. Preparation of tert-butylN-[(9R,13S)-3-(²H₃)methyl-9-methyl-8-oxo(10,11-²H₂)3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate

tert-ButylN-[(9R,10E,13S)-3-(²H₃)methyl-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate(153 mg, 0.382 mmol), prepared as described in Example 33E, in CD₃OD (7ml), under N₂ was added Pd/C (0.0382 mmol), the resulting solution waspurged and refilled with N₂, then refilled with D2 (3×), and stirred atrt at 50 psi D2 for 65 h. The reaction mixture was filtered throughCELITE® followed by a syringe filter. The filtrate was concentrated todryness and dried further under vacuum to give tert-butylN-[(9R,13S)-3-(²H₃)methyl-9-methyl-8-oxo(10,11-²H₂)3,4,7,15tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamateas a light brown solid (143.4 mg, 88.2%). MS(ESI) m/z: 405.3 (M+H)⁺. ¹HNMR (400 MHz, CD₃OD) δ 8.68 (d, J=5.1 Hz, 1H), 7.50-7.42 (m, 3H),4.80-4.73 (m, 1H), 3.61 (q, J=7.0 Hz, 1H), 2.76-2.65 (m, 1H), 1.96-1.80(m, 1H), 1.72-1.61 (m, 1H), 1.54 (t, J=5.6 Hz, 1H), 1.42 (s, 9H), 1.18(t, J=7.0 Hz, 1H), 0.94 (d, J=7.0 Hz, 3H).

111B. Preparation of(9R,13S)-13-amino-3-(²H₃)methyl-9-methyl(10,11-²H₂)-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

CF₃COOD (0.229 ml, 2.97 mmol) was added to a solution tert-butylN-[(9R,13S)-3-(²H₃)methyl-9-methyl-8-oxo(10,11-²H₂)3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate(0.040 g, 0.099 mmol) in CD₂Cl₂ (1 ml, 15.67 mmol) at rt. After 1 h, thereaction mixture was concentrated to dryness. The residue was dissolvedin MeOH and free based by passing through two consecutive resin boundNaHCO₃ cartridges (StratoSpheres SPE; 500 mg, 0.90 mmol loading) andconcentrated. The product,(9R,13S)-13-amino-3-(²H₃)methyl-9-methyl(10,11-²H₂)-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one,was carried forward ‘as is’ to next reaction. MS(ESI) m/z: 305.2 (M+H)⁺.

111C. Preparation of(9R,13S)-13-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(²H₃)methyl-9-methyl(10,11-²H₂)-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate

To a vial (4 ml) containing a suspension6-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]pyrimidin-4-ol(0.027 g, 0.083 mmol), prepared as described in Intermediate 10, in ACN(1 ml) was added HATU (0.041 g, 0.108 mmol) and DBU (0.019 ml, 0.124mmol). After 30 min, (9R,13S)-13-amino-3-(²H₃)methyl-9-methyl(10,11-²H₂)-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(0.025 g, 0.082 mmol) in DMF (1.0 ml) was added at rt. After 2 h, thecrude mixture was purified by reverse phase chromatography (PHENOMENEX®Luna Axia C18 5μ 30×100 mm column, Solvent A: 20% ACN—80% H₂O— 0.1% TFA;Solvent B: 80% ACN—20% H₂O— 0.1% TFA) to give(9R,13S)-13-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(²H₃)methyl-9-methy(10,11-²H₂)-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate (19.2 mg, 30.8%) as awhite solid. MS(ESI) m/z: 613.2 (M+H)⁺. ¹H NMR (400 MHz, CD₃OD) δ8.90-8.75 (m, 2H), 8.35 (s, 1H), 7.87 (d, J=7.7 Hz, 1H), 7.76 (br. s.,1H), 7.64-7.52 (m, 3H), 6.63 (s, 1H), 6.00 (d, J=12.1 Hz, 1H), 2.76-2.68(m, 1H), 2.37-2.29 (m, 1H), 2.08-2.02 (m, 1H), 1.61 (t, J=6.2 Hz, 1H),1.46 (d, J=4.4 Hz, 1H), 1.03 (d, J=6.8 Hz, 3H). Analytical HPLC (MethodA): RT=7.90 min, purity=99.1%; Factor XIa Ki=0.1 nM, Plasma KallikreinKi=8 nM.

Example 112 Preparation of(9R,13S)-13-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl(10,11-²H₂)-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate

112A. Preparation of tert-butylN-[(9R,13S)-3-(difluoromethyl)-9-methyl-8-oxo(10,11-²H₂)-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate

tert-ButylN-[(9R,10E,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate(180 mg, 0.415 mmol), prepared as described in Example 30E, in CD₃OD (7ml), under N₂ was added Pd/C (0.0415 mmol), the resulting solution waspurged and refilled with N₂ and refilled with D2 (3×), then stirred atrt at 50 psi D2 for 60 h. The reaction mixture was filtered throughCELITE® followed by a syringe filter. The filtrate was concentrated todryness and dried further under vacuum to give tert-butylN-[(9R,13S)-3-(difluoromethyl)-9-methyl-8-oxo(10,11-²H₂)-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamateas a light brown solid (167 mg, 88.9%). MS(ESI) m/z: 438.3 (M+H)⁺. ¹HNMR (400 MHz, CD₃OD) δ 8.70 (d, J=5.5 Hz, 1H), 7.79 (s, 1H), 7.72 (s,1H), 7.65 (d, J=2.0 Hz, 1H), 7.52-7.44 (m, 4H), 3.61 (q, J=7.0 Hz, 1H),2.69 (t, J=6.8 Hz, 2H), 1.91-1.82 (m, 2H), 1.74-1.64 (m, 2H), 1.53 (t,J=5.8 Hz, 2H), 1.42 (s, 13H), 1.33-1.14 (m, 6H), 0.94 (d, J=7.0 Hz, 6H).

112B. Preparation of(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl(10,11-²H₂)-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

CF₃COOD (0.211 ml, 2.74 mmol) was added to a solution tert-butylN-[(9R,13S)-3-(difluoromethyl)-9-methyl-8-oxo(10,11-²H₂)-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate(0.040 g, 0.091 mmol) in CD₂Cl₂ (1 ml, 15.67 mmol) at rt. After 1 h, thereaction mixture was concentrated to dryness. The residue was dissolvedin MeOH and free based by passing through two consecutive resin boundNaHCO₃ cartridges (StratoSpheres SPE; 500 mg, 0.90 mmol loading) andconcentrated. The product,(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl(10,11-²H₂)-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onewas carried forward as is to next reaction. MS(ESI) m/z: 338.2 (M+H)⁺.

112C. Preparation of(9R,13S)-13-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl(10,11-²H₂)-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate

To a vial (4 ml) containing a suspension6-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]pyrimidin-4-ol(0.024 g, 0.074 mmol), prepared as described in Intermediate 10, in ACN(1 ml) was added HATU (0.037 g, 0.096 mmol) and DBU (0.017 ml, 0.111mmol). After 30 min,(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl(10,11-²H₂)-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(0.025 g, 0.074 mmol) in DMF (1.0 ml) was added at rt. After 2 h, thecrude mixture was purified by reverse phase chromatography (PHENOMENEX®Luna Axia C18 5μ 30×100 mm column, Solvent A: 20% ACN—80% H₂O— 0.1% TFA;Solvent B: 80% ACN—20% H₂O— 0.1% TFA) to give(9R,13S)-13-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl(10,11-²H₂)-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate (16.8 mg, 29.8%) as a white solid. MS(ESI) m/z: 646.3(M+H)⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.91 (s, 1H), 8.78 (d, J=5.1 Hz, 1H),8.34 (s, 1H), 7.91-7.85 (m, 1H), 7.83-7.67 (m, 3H), 7.58-7.52 (m, 2H),6.63 (s, 1H), 6.04 (dd, J=12.8, 4.6 Hz, 1H), 2.73 (quin, J=6.8 Hz, 1H),2.31 (td, J=12.8, 4.0 Hz, 1H), 2.07-1.99 (m, 1H), 1.59 (t, J=6.1 Hz,1H), 1.48 (d, J=4.8 Hz, 1H), 1.01 (d, J=6.8 Hz, 3H). Analytical HPLC(Method A): RT=8.81 min, purity=100%; Factor XIa Ki=0.1 nM, PlasmaKallikrein Ki=6 nM.

Example 113 Preparation of(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl)}-3-(difluoromethyl)-9-methyl(10,11-²H₂)-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate

(9R,13S)-13-{4-[5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl(10,11-²H₂)-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onewas prepared in a similar manner as the procedure described in Example112, by using6-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol(0.023 g, 0.075 mmol), prepared in Intermediate 9, to give(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl(10,11-²H₂)-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate as a white solid (20.4 mg, 36.3%). MS(ESI) m/z: 628.1(M+H)⁺. ¹H NMR (400 MHz, CD₃OD) 8.91 (s, 1H), 8.77 (d, J=5.1 Hz, 1H),8.36 (s, 1H), 7.91 (d, J=2.4 Hz, 1H), 7.83-7.65 (m, 5H), 7.58-7.52 (m,1H), 6.39 (d, J=0.4 Hz, 1H), 6.03 (dd, J=12.8, 4.6 Hz, 1H), 2.74 (t,J=6.7 Hz, 1H), 2.32 (td, J=12.9, 4.0 Hz, 1H), 2.07-1.98 (m, 1H), 1.59(t, J=6.2 Hz, 1H), 1.48 (d, J=4.8 Hz, 1H), 1.02 (d, J=7.0 Hz, 3H).Analytical HPLC (Method A): RT=8.81 min, purity=99.3%; Factor XIa Ki=0.1nM, Plasma Kallikrein Ki=25 nM.

Example 114 Preparation of(10R,14S)-14-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-10-methyl-3,8,16-triazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-9-one,bis-trifluoroacetate

To a vial (4 ml) containing a suspension6-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol(0.021 g, 0.067 mmol), prepared as described in Intermediate 9, in ACN(1 ml) was added HATU (0.033 g, 0.088 mmol) and DBU (0.015 ml, 0.101mmol). After 30 min,(10R,14S)-14-amino-10-methyl-3,8,16-triazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-9-one(0.020 g, 0.067 mmol), prepared as described in Intermediate 38, in DMF(1.0 ml) was added at rt. After 4 h, the crude mixture was purified byreverse phase chromatography (PHENOMENEX® Luna Axia C18 5μ30×100 mmcolumn, Solvent A: 20% ACN—80% H₂O— 0.1% TFA; Solvent B: 80% ACN—20%H₂O— 0.1% TFA) to give(10R,14S)-14-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-10-methyl-3,8,16-triazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-9-one,bis-trifluoroacetate (3.7 mg, 6.72%) as a white solid. MS(ESI) m/z:587.1 (M+H)⁺. ¹H NMR (500 MHz, CD₃OD) δ 9.02 (s, 1H), 8.77 (d, J=4.8 Hz,1H), 8.66 (d, J=4.8 Hz, 1H), 8.37 (s, 1H), 7.94-7.88 (m, 2H), 7.79-7.74(m, 2H), 7.71-7.67 (m, 2H), 7.59 (dd, J=8.1, 4.8 Hz, 1H), 6.39 (s, 1H),6.09 (dd, J=12.8, 5.1 Hz, 1H), 2.76 (br. s., 1H), 2.28 (t, J=12.8 Hz,1H), 2.10-2.03 (m, 2H), 1.62-1.53 (m, 2H), 1.01 (d, J=7.0 Hz, 3H), 0.66(br. s., 1H). Analytical HPLC (Method A): RT=7.60 min, purity=99.0%;Factor XIa Ki=3.3 nM, Plasma Kallikrein Ki=200 nM.

Example 115 Preparation of(9R,13S)-13-[4-(5-chloro-1-methyl-1H-indazol-7-yl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3-(²H₃)methyl-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate

To a vial (4 ml) containing a suspension6-(5-chloro-1-methyl-1H-indazol-7-yl)pyrimidin-4-ol (0.017 g, 0.066mmol), prepared as described in Intermediate 22, in ACN (1 ml) was addedHATU (0.033 g, 0.086 mmol) and DBU (0.015 ml, 0.099 mmol). After 30 min,(9R,13S)-13-amino-3-(²H₃)methyl-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(0.020 g, 0.066 mmol), prepared as described in Intermediate 33, in DMF(1.0 ml) was added at rt. After 4 h, the crude mixture was purified byreverse phase chromatography (PHENOMENEX® Luna Axia C18 5μ 30×100 mmcolumn, Solvent A: 20% ACN—80% H₂O— 0.1% TFA; Solvent B: 80% ACN—20%H₂O— 0.1% TFA) to give(9R,13S)-13-[4-(5-chloro-1-methyl-1H-indazol-7-yl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3-(²H₃)methyl-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate (7.2 mg, 16.3%) as a white solid. MS(ESI) m/z: 587.1(M+H)⁺. ¹H NMR (500 MHz, CD₃OD) δ 9.10 (s, 1H), 8.81 (d, J=5.3 Hz, 1H),8.11 (s, 1H), 7.94 (d, J=2.0 Hz, 1H), 7.87 (s, 1H), 7.66 (d, J=5.1 Hz,1H), 7.59-7.55 (m, 1H), 7.50 (d, J=1.8 Hz, 1H), 6.80 (s, 1H), 6.10 (dd,J=12.4, 4.1 Hz, 1H), 4.01-3.96 (m, 3H), 2.76 (dd, J=6.6, 3.1 Hz, 1H),2.51-2.46 (m, 1H), 2.22-2.11 (m, 2H), 1.72-1.67 (m, 1H), 1.56 (br. s.,1H), 1.08 (d, J=7.0 Hz, 3H), 0.85 (br. s., 1H). Analytical HPLC (MethodA): RT=7.41 min, purity=100.0%; Factor XIa Ki=113 nM.

Example 116 Preparation of(9R,13S)-13-{4-[5-chloro-2-(1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

To a vial (4 ml) containing a suspension6-[5-chloro-2-(1H-1,2,3-triazol-1-yl) phenyl]pyrimidin-4-ol (0.016 g,0.060 mmol), prepared as described in Intermediate 8, in ACN (1 ml) wasadded HATU (0.030 g, 0.078 mmol) and DBU (0.014 ml, 0.090 mmol). After30 min(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(0.020 g, 0.060 mmol), prepared as described in Intermediate 35, in DMF(1.0 ml) was added at rt. After 4 h, the crude mixture was purified byreverse phase chromatography (PHENOMENEX® Luna Axia C18 5μ 30×100 mmcolumn, Solvent A: 20% ACN—80% H₂O— 0.1% TFA; Solvent B: 80% ACN—20%H₂O— 0.1% TFA) to give(9R,13S)-13-[4-(5-chloro-1-methyl-1H-indazol-7-yl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3-(²H₃)methyl-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-oneas a white solid. MS(ESI) m/z: 591.3 (M+H)⁺. ¹H NMR (400 MHz, CD₃OD) δ8.22 (d, J=1.8 Hz, 2H), 7.90-7.72 (m, 5H), 7.66-7.50 (m, 4H), 7.41 (d,J=7.5 Hz, 1H), 6.27 (s, 1H), 5.83 (dd, J=12.9, 3.4 Hz, 1H), 2.57-2.47(m, 1H), 2.41-2.31 (m, 1H), 2.18-2.06 (m, 1H), 1.90 (dd, J=9.5, 5.1 Hz,1H), 1.64-1.52 (m, 2H), 1.27-1.11 (m, 4H). Analytical HPLC (Method A):RT=8.82 min, purity=98.4%; Factor XIa Ki=0.72 nM, Plasma KallikreinKi=120 nM.

Example 117 Preparation of(9R,13S)-13-[4-(5-chloro-1-methyl-1H-indazol-7-yl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3-(difluoromethyl)-9-methyl-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

To a vial (4 ml) containing a suspension of6-(5-chloro-1-methyl-1H-indazol-7-yl) pyrimidin-4-ol. (0.016 g, 0.060mmol), prepared as described in Intermediate 22, in ACN (1 ml) was addedHATU (0.030 g, 0.078 mmol) and DBU (0.014 ml, 0.090 mmol). After 30 min(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(0.020 g, 0.060 mmol), prepared as described in Intermediate 35, in DMF(1.0 ml) was added at rt. After 4 h, the crude mixture was purified byreverse phase chromatography (PHENOMENEX® Luna Axia C18 5μ 30×100 mmcolumn, Solvent A: 20% ACN—80% H₂O— 0.1% TFA; Solvent B: 80% ACN—20%H₂O— 0.1% TFA) to give(9R,13S)-13-[4-(5-chloro-1-methyl-1H-indazol-7-yl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3-(difluoromethyl)-9-methyl-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(11 mg, 30.2%) as a white solid. MS(ESI) m/z: 578.2 (M+H)⁺. ¹H NMR (400MHz, CD₃OD) δ 8.36 (s, 1H), 7.95 (s, 1H), 7.79-7.74 (m, 2H), 7.66 (s,1H), 7.54-7.38 (m, 4H), 7.34 (d, J=2.0 Hz, 1H), 6.67 (s, 1H), 5.83 (dd,J=13.0, 3.3 Hz, 1H), 3.79 (s, 3H), 2.41-2.32 (m, 2H), 2.11 (d, J=12.5Hz, 1H), 1.83-1.76 (m, 1H), 1.53-1.45 (m, 2H), 1.16-1.03 (m, 4H).Analytical HPLC (Method A): RT=9.56 min, purity=100%; Factor XIa Ki=90nM, Plasma Kallikrein Ki=3,800 nM.

Example 118 Preparation of(10R,14S)-14-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-10-methyl-3,8,16-triazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-9-onebis-trifluoroacetate

To a vial (4 ml) containing a suspension6-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]pyrimidin-4-ol(0.028 g, 0.084 mmol), prepared as described in Intermediate 10, in ACN(1 ml) was added HATU (0.042 g, 0.11 mmol) and DBU (0.019 ml, 0.127mmol). After 30 min,10R,14S)-14-amino-10-methyl-3,8,16-triazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-9-one(0.025 g, 0.084 mmol), prepared as described in Intermediate 39, in DMF(1.0 ml) was added at rt. After stirring overnight, the crude mixturewas purified by reverse phase chromatography (PHENOMENEX® Luna Axia C185μ i 30×100 mm column, Solvent A: 20% ACN—80% H₂O— 0.1% TFA; Solvent B:80% ACN—20% H₂O— 0.1% TFA) to give, after concentration andlyophilization(10R,14S)-14-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-10-methyl-3,8,16-triazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-9-one,bis-trifluoroacetate (13 mg, 17.6%) as a white solid. MS(ESI) m/z: 611.2(M+H)⁺ and 613.1 (M+2+H)⁺. ¹H NMR (400 MHz, CD₃OD) δ ¹H NMR (500 MHz,CD₃OD-d4) d 8.98 (s, 1H), 8.86-8.83 (m, 1H), 8.75-8.71 (m, 1H), 8.37 (s,1H), 7.98 (s, 1H), 7.95-7.87 (m, 2H), 7.79-7.71 (m, 2H), 7.59-7.57 (m,1H), 6.64 (s, 1H), 6.08 (dd, J=12.4, 5.0 Hz, 1H), 2.77 (br. s., 1H),2.35-2.28 (m, 1H), 2.13-2.02 (m, 2H), 1.61-1.55 (m, 2H), 1.29 (d, J=6.9Hz, 1H), 1.00 (d, J=7.2 Hz, 3H), 0.66 (br. s., 1H). Analytical HPLC(Method A): RT=7.11 min, purity=97.5%; Factor XIa Ki=1.4 nM, PlasmaKallikrein Ki=73 nM.

Example 119 Preparation of(9R,13S)-3-(difluoromethyl)-9-methyl-13-(4-{5-methyl-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,4,7,17-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

119A. Preparation of4-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline

2-Bromo-4-methylaniline (3 g, 16.12 mmol), bis(pinacolato)diboron (6.14g, 24.19 mmol), KOAc (4.07 g, 41.4 mmol) were added to DMSO (9 mL) underN₂ atm and then degassed for 10 min. Pd(dppf)Cl₂.CH₂Cl₂ Adduct (0.395 g,0.484 mmol) was added and the resulting suspension was stirred overnightat 80° C. The reaction mixture was partitioned between DCM and water.The organic layer was washed with brine, dried over Na₂SO₄, filtered,and concentrated then purified normal phase chromatography using hexaneand EtOAc as eluents to give4-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (3.52 g,94% yield) as a clear oil which solidified into a white solid uponstanding. MS(ESI) m/z: 152.3 (M-C₆H₁₀+H)⁺. ¹H NMR (400 MHz, CDCl₃-d) δ7.43 (d, J=1.8 Hz, 1H), 7.04 (dd, J=8.3, 2.3 Hz, 1H), 6.55 (d, J=8.1 Hz,1H), 4.60 (br. s., 2H), 2.23-2.20 (m, 3H), 1.38-1.32 (m, 12H).

119B. Preparation of 2-(6-methoxypyrimidin-4-yl)-4-methylaniline

To a RBF equipped with a reflux condenser containing DME (42.9 mL), EtOH(5.36 mL) was added 4-chloro-6-methoxypyrimidine (1.55 g, 10.72 mmol),4-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (2.5 g,10.72 mmol) and 2 M aq Na₂CO₃ (5.36 mL, 10.72 mmol). The mixture waspurged with Ar for 10 min then PdCl₂(dppf)-CH₂Cl₂ Adduct (0.876 g, 1.072mmol) was added and the reaction mixture heated at 90° C. After 2 h, thereaction was diluted with water and extracted with EtOAc. The organiclayer washed with brine and concentrated to give a brown oil. The crudeproduct was purified by normal phase chromatography using heptane andEtOAc as eluents to give 2-(6-methoxypyrimidin-4-yl)-4-methylaniline(670 mg, 29%) as a solid. MS(ESI) m/z: 216.1 (M+H)⁺. ¹H NMR (500 MHz,CDCl₃-d) δ 8.79 (d, J=1.1 Hz, 1H), 7.33 (d, J=1.4 Hz, 1H), 7.08-7.01 (m,2H), 6.67 (d, J=8.3 Hz, 1H), 5.68 (br. s., 2H), 4.03 (s, 3H), 2.29 (s,3H).

119C. Preparation of4-methoxy-6-(5-methyl-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)pyrimidine

To a cooled (0° C.), clear, yellow solution of2-(6-methoxypyrimidin-4-yl)-4-methylaniline (0.670 g, 3.11 mmol) in ACN(44.5 mL) was added isoamylnitrite (0.63 mL, 4.67 mmol), followed bydropwise addition of TMSN₃ (0.62 mL, 4.67 mmol). After 10 min, the coldbath was removed, and the reaction allowed to warm to rt. After 4.5 h,Cu₂O (0.045 g, 0.311 mmol) was added. After a few min,3,3,3-trifluoroprop-1-yne (0.293 g, 3.11 mmol) gas was bubbled into thedark green solution at rt. After 1 h, the reaction was diluted with DCMand washed with sat NH₄Cl, brine, dried over MgSO₄, filtered andconcentrated to give a brown oil. The crude product was purified bynormal phase chromatography using heptane and EtOAc as eluents to give4-methoxy-6-(5-methyl-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)pyrimidine(941 mg, 90%) as a solid. MS(ESI) m/z: 336.1 (M+H)⁺. ¹H NMR (500 MHz,CDCl₃-d) δ 8.63 (s, 1H), 7.98 (s, 1H), 7.56 (s, 1H), 7.45 (s, 2H), 6.58(s, 1H), 3.97 (s, 3H), 2.53 (s, 3H).

119D. Preparation of6-(5-methyl-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol

A clear, yellow solution of4-methoxy-6-(5-methyl-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)pyrimidine(0.941 g, 2.81 mmol) in AcOH (14.03 mL) and 48% aq HBr (15.88 mL, 140mmol) was warmed to 85° C. After 3 h, the reaction was cooled to rt andconcentrated. The yellow gum dissolved in EtOAc, washed with sat NaHCO₃,brine, dried over Na₂SO₄, filtered, and concentrated. Et₂O (3 mL) wasadded, sonicated, and filtered. The solid rinsed with Et₂O (5 mL),air-dried with suction overnight to afford6-(5-methyl-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol(0.609 g, 67.5% yield) as a light yellow solid. MS(ESI) m/z: 322.1(M+H)⁺. ¹H NMR (400 MHz, CDCl₃) δ 12.90 (br. s., 1H), 8.06 (s, 1H), 7.93(d, J=0.7 Hz, 1H), 7.57-7.40 (m, 3H), 6.51 (d, J=0.9 Hz, 1H), 2.53 (s,3H).

119E. Preparation of(9R,13S)-3-(difluoromethyl)-9-methyl-13-(4-{5-methyl-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,4,7,17-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate

(9R,13S)-3-(Difluoromethyl)-9-methyl-13-(4-{5-methyl-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,4,7,17-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate (13 mg, 23%) was prepared in a similar manner asExample 56, using6-(5-methyl-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-oland(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,17-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one,prepared as described in Intermediate 37. MS(ESI) m/z: 640.2 (M+H)⁺. ¹HNMR (400 MHz, CD₃OD) δ 8.67 (s, 1H), 8.62-8.57 (m, 1H), 8.31-8.10 (m,3H), 8.00-7.83 (m, 2H), 7.69 (s, 2H), 7.45 (d, J=0.9 Hz, 2H), 7.02 (dd,J=5.1, 1.5 Hz, 1H), 6.39 (s, 1H), 5.71-5.62 (m, 1H), 2.60-2.53 (m, 1H),2.42 (s, 3H), 2.27 (d, J=6.6 Hz, 1H), 2.03-1.93 (m, 2H), 1.56 (dd,J=13.4, 5.1 Hz, 1H), 1.31-1.19 (m, 2H), 1.03 (d, J=6.8 Hz, 3H).Analytical HPLC (Method A): RT=8.90 min, purity=99%; Factor XIa Ki=1.1nM, Plasma Kallikrein Ki=340 nM.

Example 120 Preparation of(9R,13S)-13-{4-[5-chloro-2-(1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-5-(trifluoromethyl)-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

A TFA/DMSO solution was prepared by dissolving TFA (10 μL) in DMSO (2.5mL). To a separate vial containing a mixture of(9R,13S)-13-{4-[5-chloro-2-(1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate (0.0084 g, 0.013 mmol), prepared as described inExample 133, and Zn(SO₂CF₃)₂ (8.31 mg, 0.025 mmol) was added DMSO (0.25mL). Next, 0.25 mL of the TFA/DMSO solution was added to give a clear,yellow solution. Then, 70% aq t-BuOOH (5.21 μl, 0.038 mmol) was added.After 2 h, additional Zn(SO₂CF₃)₂ (16.6 mg, 0.050 mmol) was added. After30 min, additional 70% aq t-BuOOH (10.4 μl, 0.076 mmol) was added. After1 h, the reaction was stopped. MeOH (1.5 mL) was added to the reactionmixture and it was purified by reverse phase chromatography to provide(9R,13S)-13-{4-[5-chloro-2-(1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-5-(trifluoromethyl)-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(0.0024 g, 30% yield) as a white solid. MS(ESI) m/z: 624.4 (M+H)⁺, 626.4(M+2+H)⁺. A mixture of atropisomers were observed by ¹H NMR and ¹⁹F NMR.¹H NMR (500 MHz, CD₃OD) δ 9.09-9.06 (m, 0.5H), 9.03-9.00 (m, 0.5H), 8.75(d, J=5.0 Hz, 0.5H), 8.72 (d, J=5.0 Hz, 0.5H), 8.33 (s, 0.5H), 8.25 (s,0.5H), 7.87 (br. s., 0.5H), 7.80 (br. s., 0.5H), 7.76-7.67 (m, 3H), 7.64(d, J=2.2 Hz, 0.5H), 7.61 (d, J=2.2 Hz, 0.5H), 7.55-7.48 (m, 2H),6.06-5.97 (m, 1H), 4.06 (s, 1.5H), 4.05 (s, 1.5H), 2.77-2.68 (m, 1H),2.33-2.24 (m, 1H), 2.14-1.99 (m, 2H), 1.65-1.56 (m, 1H), 1.56-1.44 (m,1H), 1.02-0.97 (m, 3H), 0.68-0.55 (m, 1H). ¹⁹F NMR (471 MHz, CD₃OD) δ−60.90 (s, 1F), −60.94 (s, 1F). Analytical HPLC (Method A): RT=7.55 min,purity=97.9%; Factor XIa Ki=110 nM.

Example 121 Preparation of(10R,14S)-14-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-10-methyl-3,8,16-triazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-9-one,bis-trifluoroacetate

To a vial (4 ml) containing a suspension6-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}pyrimidin-4-ol(0.027 g, 0.078 mmol), prepared as described in Intermediate 15, in ACN(2 ml) was added HATU (0.038 g, 0.101 mmol) and DBU (0.018 ml, 0.116mmol). After 30 min,(10R,14S)-14-amino-10-methyl-3,8,16-triazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-9-one(0.023 g, 0.078 mmol), prepared as described in Intermediate 39, in ACN(1.0 ml) was added at rt. After 4 h, the crude mixture was purified byreverse phase chromatography (PHENOMENEX® Luna Axia C18 5μ 30×100 mmcolumn, Solvent A: 20% ACN—80% H₂O— 0.1% TFA; Solvent B: 80% ACN—20%H₂O— 0.1% TFA) to give(10R,14S)-14-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-10-methyl-3,8,16-triazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-9-one,bis-trifluoroacetate (18 mg, 26.8%) as a white solid. MS(ESI) m/z: 621.2(M+H)⁺ and 623.1 (M+2+H)⁺. ¹H NMR (500 MHz, CD₃OD) δ 8.82 (s, 1H), 8.72(d, J=0.8 Hz, 1H), 8.63 (d, J=5.0 Hz, 1H), 8.54 (dd, J=5.0, 1.4 Hz, 1H),7.80-7.78 (m, 2H), 7.70 (dd, J=8.1, 1.5 Hz, 1H), 7.68-7.64 (m, 1H),7.61-7.57 (m, 2H), 7.51 (dd, J=8.0, 5.0 Hz, 1H), 6.33 (d, J=0.8 Hz, 1H),5.95 (dd, J=12.7, 4.7 Hz, 1H), 2.66-2.61 (m, 1H), 2.13 (t, J=12.7 Hz,1H), 1.91 (t, J=9.9 Hz, 2H), 1.47-1.39 (m, 2H), 0.87 (d, J=7.2 Hz, 3H).Analytical HPLC (Method A): RT=8.18 min, purity=98.3%; Factor XIa Ki=2.8nM, Plasma Kallikrein Ki=190 nM.

Example 122 Preparation of(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,16-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

To a vial (4 ml) containing a suspension6-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol(0.014 g, 0.046 mmol), prepared as described in Intermediate 9, in ACN(1 ml) was added HATU (0.019 g, 0.051 mmol) and DBU (0.009 ml, 0.060mmol). After 20 min,(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,16-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(0.0155 g, 0.046 mmol), prepared as described in Intermediate 43, in DMF(1.0 ml) was added at rt. After 3 h, the crude mixture was purified byreverse phase (PHENOMENEX® Luna Axia C18 5μ 30×100 mm column, Solvent A:20% ACN—80% H₂O— 0.1% TFA; Solvent B: 80% ACN—20% H₂O— 0.1% TFA) to give(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,16-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(1.7 mg, 5.86%). MS(ESI) m/z: 626 (M+H)⁺. ¹H NMR (500 MHz, DMSO-d₆) δ9.35 (s, 1H), 8.74 (s, 1H), 8.63 (d, J=1.7 Hz, 1H), 8.60-8.53 (m, 2H),8.12-7.97 (m, 2H), 7.93-7.86 (m, 2H), 7.85-7.71 (m, 2H), 6.41 (s, 1H),5.57 (d, J=9.9 Hz, 1H), 2.46-2.39 (m, 1H), 2.04-1.95 (m, 1H), 1.79 (d,J=10.7 Hz, 1H), 1.42 (d, J=6.9 Hz, 1H), 1.24 (br. s., 1H), 0.99 (d,J=6.6 Hz, 4H). Analytical HPLC (Method C): RT=1.52 min, purity=100.0%;Factor XIa Ki=0.16 nM, Plasma Kallikrein Ki=34 nM.

Example 123 Preparation of6-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-3-[(9R,13S)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-3,4-dihydropyrimidin-4-one

123A. Preparation of(9R,13S)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-amine

To a solution of(9R,13S)-13-amino-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onedihydrochloride (45 mg, 0.121 mmol), prepared as described inIntermediate 32, in THF (3022 μl) was added BH₃.THF complex (1813 μl,1.813 mmol). The reaction was sealed and heated at 60° C. for 4.5 h.MeOH was added, followed by addition of 1.25 M HCl in MeOH (2 ml). Themixture was sealed and heated at 60° C. for 1 h. Another 0.5 mL of HClin MeOH was added and heated at 60° C. for 1 h then cooled down to rtovernight. Another 0.5 mL of 4 N HCl in dioxane was added and thesolution was heated at 65° C. for 5 h. The reaction mixture wasconcentrated. The residue was dissolved in MeOH, purified by reversephase prep HPLC. After concentration and passing through NaHCO₃cartridge,(9R,13S)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-amine(28 mg, 81%) was obtained as an colorless oil. MS(ESI) m/z: 286.5(M+H)⁺.

123B. Preparation of6-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-3-[(9R,13S)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-3,4-dihydropyrimidin-4-one

6-[3-Chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-3-[(9R,13S)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-3,4-dihydropyrimidin-4-onetrifluoroacetate (12.5 mg, 30.4% yield) was prepared in a similar manneras the procedure described in Example 56 by using(9R,13S)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-amine(6.5 mg, 0.020 mmol). ¹H NMR (400 MHz, CDCl₃) δ 8.95 (s, 1H), 8.84 (d,J=5.1 Hz, 1H), 8.35 (s, 1H), 8.09-8.04 (m, 1H), 7.90-7.83 (m, 1H), 7.64(s, 1H), 7.59-7.53 (m, 2H), 6.62 (s, 1H), 6.17 (dd, J=12.5, 4.8 Hz, 1H),4.02 (s, 3H), 2.97 (d, J=10.6 Hz, 1H), 2.53 (br. s., 1H), 2.34-2.19 (m,1H), 2.17-2.05 (m, 1H), 2.04-1.75 (m, 2H), 1.56 (t, J=12.3 Hz, 1H), 1.23(br. s., 1H), 0.86 (d, J=7.3 Hz, 3H), 0.75-0.40 (m, 1H). MS(ESI) m/z:594.2 (M+H)⁺. Analytical HPLC (Method A): RT=6.97 min, purity=99.1%;Factor XIa Ki=2 nM, Plasma Kallikrein Ki=690 nM.

Example 124 Preparation of(9S,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-10-fluoro-9-methyl-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

124A. Preparation of tert-butylN-[(9S,13S)-3-(difluoromethyl)-10-fluoro-9-methyl-8-oxo3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate

Fe₂(C₂O₄)₃.6H₂O (2.797 g, 5.78 mmol) was added to a RBF containing H₂O(30 ml). The suspension was warmed by a water bath (50° C.) to aiddissolution. After 3 h, the clear yellow solution was cooled to 0° C.and purged with Ar. After 20 min, SELECTFLUOR® (2.048 g, 5.78 mmol) inACN (5 ml) was added followed by dropwise addition of tert-butylN-[(9R,10E,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate(0.500 g, 1.156 mmol), prepared as described in Example 35D, in ACN (10ml). After 5 min, NaBH₄ (0.350 g, 9.25 mmol) was added in two separateportions over a 5 min period. After 15 min, the reaction mixture wasallowed to come to rt. After 1 h, the reaction mixture was quenched withaqueous NH₄OH (28-30%; 15 mL). After 30 min, the reaction mixture wasfiltered and the collected solids washed with EtOAc. The combinedorganics was washed with brine, dried over Na₂SO₄, filtered, andconcentrated to give a crude mixture of isomers. The material wassubjected chiral purification using CHIRALPAK® IC, 21×250 mm, 5μ, using10% MeOH/90% CO₂ at 75 ml/min, 150 Bar, 40° C. The early eluting isomerwas assigned as tert-butylN-[(9S,13S)-3-(difluoromethyl)-10-fluoro-9-methyl-8-oxo-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate(99.5% ee; 38 mg, 7.26%) and the second eluting isomer, tert-butylN-[(9R,13S)-3-(difluoromethyl)-11-fluoro-9-methyl-8-oxo-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate(99.5% ee; 34 mg, 6.50%). MS(ESI) m/z: 397 (M-tBu)⁺.

124B.(9S,13S)-13-{4-[5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-10-fluoro-9-methyl-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

The early eluting isomer tert-butylN-[(9S,13S)-3-(difluoromethyl)-10-fluoro-9-methyl-8-oxo-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate(0.038 g, 0.084 mmol) was treated with HCl (4.0 M in dioxane) (0.420 ml,1.680 mmol). A minimum amount of MeOH was added to aid dissolution.After 2 h, the reaction mixture was concentrated to dryness. The residuewas dissolved in MeOH and passed through a NaHCO₃ cartridge(StratoSpheres SPE; 500 mg, 0.90 mmol loading). The filtrate wasconcentrated and the free base temporarily set aside. Separately, flaskcontaining a white suspension of6-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl) pyrimidin-4-ol(0.026 g, 0.084 mmol), prepared as described in Intermediate 9, in ACN(1.120 ml) was added HATU (0.035 g, 0.092 mmol) and DBU (0.016 ml, 0.109mmol). After 20 min, the free base in DMF (1 mL) was added and theresulting suspension was stirred at rt overnight. The reaction mixturewas purified reverse phase chromatography (SunFire C18 5μ 30×100 mmcolumn, 10-minute gradient; Solvent A: 20% ACN—80% H₂O— 0.1% TFA;Solvent B: 80% ACN—20% H₂O— 0.1% TFA). The pure fractions were liberatedof organics and the remaining aqueous phase freeze-dried to give(9S,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-10-fluoro-9-methyl-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(18.2 mg, 33.3%) as a white solid. MS(ESI) m/z: 643 (M+H)⁺. ¹H NMR (500MHz, CD₃OD) δ 8.83 (s, 1H), 8.40-8.38 (m, 1H), 7.93 (d, J=2.2 Hz, 1H),7.80-7.75 (m, 2H), 7.71-7.68 (m, 1H), 7.66-7.62 (m, 3H), 7.54 (d, J=7.7Hz, 1H), 7.28 (d, J=8.0 Hz, 1H), 6.46 (d, J=0.8 Hz, 1H), 5.92 (dd,J=13.3, 4.5 Hz, 1H), 5.38-5.25 (m, 1H), 3.19-3.14 (m, 1H), 2.48-2.41 (m,1H), 2.27 (ddt, J=12.9, 8.7, 4.2 Hz, 1H), 1.85-1.75 (m, 1H), 1.05 (d,J=6.9 Hz, 3H), 0.99-0.83 (m, 1H). Analytical HPLC (Method A): RT=9.3min, purity=99.5%; Factor XIa Ki=0.1 nM, Plasma Kallikrein Ki=24 nM.

Example 125 Preparation of(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-11-fluoro-9-methyl-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

The second eluting isomer from Example 124A, tert-butylN-[(9R,13S)-3-(difluoromethyl)-11-fluoro-9-methyl-8-oxo-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate(0.034 g, 0.075 mmol) was treated with HCl (4.0 M in dioxane) (0.376 ml,1.50 mmol). A minimum amount of MeOH was added to aid dissolution. After2 h, the reaction mixture was concentrated to dryness. The residue wasdissolved in MeOH and passed through a NaHCO₃ cartridge (StratoSpheresSPE; 500 mg, 0.90 mmol loading). The filtrate was concentrated and thefree base temporarily set aside. Separately, a flask containing a whitesuspension of6-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol(0.023 g, 0.075 mmol), prepared as described in Intermediate 9, in ACN(1.120 ml) was added HATU (0.031 g, 0.083 mmol) and DBU (0.015 ml, 0.098mmol). After 20 min, the free base in DMF (1 mL) was added and theresulting suspension was stirred at rts overnight. The reaction mixturewas purified reverse phase chromatography (SunFire C18 5μ 30×100 mmcolumn, 10-minute gradient; Solvent A: 20% ACN—80% H₂O— 0.1% TFA;Solvent B: 80% ACN—20% H₂O— 0.1% TFA). The pure fractions wereconcentrated to remove most of the ACN and the remaining aqueous phasefreeze-dried to give(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-11-fluoro-9-methyl-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(8.9 mg, 18.2%) as a white solid. MS(ESI) m/z: 643 (M+H)⁺. ¹H NMR (500MHz, CD₃OD) δ 8.35 (s, 1H), 8.20 (s, 1H), 7.88 (d, J=2.5 Hz, 1H), 7.80(s, 1H), 7.76-7.74 (m, 1H), 7.70 (s, 1H), 7.69-7.60 (m, 3H), 7.57-7.51(m, 1H), 6.44 (d, J=0.8 Hz, 1H), 6.11 (dd, J=13.1, 2.9 Hz, 1H),4.55-4.40 (m, 1H), 2.96-2.83 (m, 1H), 2.76-2.69 (m, 1H), 2.47-2.38 (m,1H), 2.21-2.12 (m, 1H), 2.03-1.92 (m, 1H), 1.26 (d, J=6.6 Hz, 3H).Analytical HPLC (Method A): 9.41 min, purity=99.5%; Factor XIa Ki=20 nM,Plasma Kallikrein Ki=2,400 nM.

Example 126 Preparation of(9S,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-10,16-difluoro-3,9-dimethyl-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

126A. Preparation ofN-[(9S,13S)-10,16-difluoro-3,9-dimethyl-8-oxo-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate

Fe₂(C₂O₄)₃.6H₂O (2.16 g, 4.46 mmol) was added to a RBF containing H₂O(30 ml). The suspension was warmed by a water bath (50° C.) to aiddissolution. After 3 h, the clear yellow solution was cooled to 0° C.and purged with Ar. After 20 min, SELECTFLUOR® (1.58 g, 4.46 mmol) inACN (5 ml) was added followed by dropwise addition of tert-butylN-[(9R,10E,13S)-16-fluoro-3,9-dimethyl-8-oxo-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate(0.370 g, 0.893 mmol), prepared as described in Intermediate 29D, in ACN(10 ml). After 5 min, NaBH₄ (0.270 g, 7.14 mmol) was added in twoseparate portions over a 5 min period. After 15 min, the reactionmixture was allowed to warm to rt. After 1 h, the reaction mixture wasquenched with 28-30% aq NH₄OH (15 mL). After 30 min, the reactionmixture was filtered, solids washed with EtOAc, organics washed withbrine, dried over Na₂SO₄, filtered, and concentrated to give a crudemixture of isomers. The material was subjected chiral purification usingCHIRALPAK® IC, 21×250 mm, 5μ, using 10% EtOH/90% CO₂ at 45 ml/min, 150Bar, 40° C. The early eluting isomer was assigned tert-butylN-[(9S,13S)-10,16-difluoro-3,9-dimethyl-8-oxo-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate(99.5% ee; 68 mg, 17.50%) and the second eluting isomer, tert-butylN-[(9R,13S)-11,16-difluoro-3,9-dimethyl-8-oxo-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate(99.5% ee; 32 mg, 8.3%). 435 (M+H)⁺.

126B. Preparation of(9S,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-10,16-difluoro-3,9-dimethyl-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

The early eluting isomer assigned tert-butylN-[(9S,13S)-10,16-difluoro-3,9-dimethyl-8-oxo-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate(0.034 g, 0.078 mmol) was treated with 4. M HCl in dioxane (0.391 ml,1.570 mmol). A minimum amount of MeOH was added to aid dissolution.After 2 h, the reaction mixture was concentrated to dryness. The residuewas dissolved in MeOH and passed through a NaHCO₃ cartridge(StratoSpheres SPE; 500 mg, 0.90 mmol loading). The filtrate wasconcentrated and the free base temporarily set aside. Separately, to aflask containing a white suspension of6-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl) phenyl)pyrimidin-4-ol(0.024 g, 0.078 mmol), prepared as described in Intermediate 9, in ACN(1.120 ml) was added HATU (0.033 g, 0.086 mmol) and DBU (0.015 ml, 0.102mmol). After 20 min, the free base in DMF (1 mL) was added and theresulting suspension was stirred at rt overnight. The reaction mixturewas purified reverse phase chromatography (SunFire C18 5μ 30×100 mmcolumn, 10-minute gradient; Solvent A: 20% ACN—80% H₂O— 0.1% TFA;Solvent B: 80% ACN—20% H₂O— 0.1% TFA). The pure fractions wereconcentrated to remove most of the ACN and the remaining aqueous phasefreeze-dried to give(9S,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-10,16-difluoro-3,9-dimethyl-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(18.5 mg, 37.5%) as a white solid. MS(ESI) m/z: 643 (M+H)⁺. ¹H NMR (500MHz, CD₃OD) δ 8.81 (s, 1H), 8.39 (s, 1H), 7.94 (d, J=2.5 Hz, 1H),7.80-7.76 (m, 1H), 7.72-7.68 (m, 1H), 7.50 (s, 1H), 7.40 (s, 1H), 7.31(dt, J=9.0, 1.8 Hz, 1H), 7.06-7.02 (m, 1H), 6.44 (s, 1H), 5.91 (dd,J=13.5, 4.4 Hz, 1H), 5.37-5.25 (m, 1H), 4.04 (s, 3H), 3.16 (ddd, J=11.3,7.1, 3.9 Hz, 1H), 2.48-2.41 (m, 1H), 2.30-2.24 (m, 1H), 1.88-1.77 (m,1H), 1.05 (d, J=6.9 Hz, 3H), 0.99-0.86 (m, 1H). Analytical HPLC (MethodA): RT=8.84 min, purity=99.5%; Factor XIa Ki=0.1 nM, Plasma KallikreinKi=12 nM.

Example 127 Preparation of(9S,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-10,16-difluoro-3,9-dimethyl-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

The early eluting isomer assigned tert-butylN-[(9S,13S)-10,16-difluoro-3,9-dimethyl-8-oxo-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate(0.034 g, 0.078 mmol), prepared as described in Example 126A was treatedwith HCl (4.0 M in dioxane) (0.391 ml, 1.570 mmol). A minimum amount ofMeOH was added to aid dissolution. After 2 h, the reaction mixture wasconcentrated to dryness. The residue was dissolved in MeOH and passedthrough a NaHCO₃ cartridge (StratoSpheres SPE; 500 mg, 0.90 mmolloading). The filtrate was concentrated and the free base temporarilyset aside. Separately, flask containing a white suspension of6-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}pyrimidin-4-ol(0.027 g, 0.078 mmol), prepared as described in Intermediate 15, in ACN(1.120 ml) was added HATU (0.033 g, 0.086 mmol) and DBU (0.015 ml, 0.102mmol). After 20 min, the free base in DMF (1 mL) was added and theresulting suspension was stirred at rt overnight. The reaction mixturewas purified reverse phase chromatography (SunFire C18 5μ 30×100 mmcolumn, 10-minute gradient; Solvent A: 20% ACN—80% H₂O— 0.1% TFA;Solvent B: 80% ACN—20% H₂O-0.1% TFA). The pure fractions were liberatedof organics and the remaining aqueous phase freeze-dried to give(9S,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-10,16-difluoro-3,9-dimethyl-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(23 mg, 44.2%) as a white solid. MS(ESI) m/z: 659.2 (M+H)⁺. ¹H NMR (500MHz, CD₃OD) δ 8.87 (d, J=0.8 Hz, 1H), 8.77 (s, 1H), 7.95 (d, J=2.2 Hz,1H), 7.82-7.78 (m, 1H), 7.76-7.71 (m, 1H), 7.50 (s, 1H), 7.39 (s, 1H),7.33-7.28 (m, 1H), 6.99 (dt, J=9.3, 1.8 Hz, 1H), 6.51 (d, J=0.8 Hz, 1H),5.91 (dd, J=13.3, 4.5 Hz, 1H), 5.37-5.24 (m, 1H), 4.07-4.02 (m, 3H),3.15 (ddd, J=11.5, 7.2, 3.9 Hz, 1H), 2.42 (tt, J=13.2, 4.0 Hz, 1H), 2.23(tt, J=13.0, 4.0 Hz, 1H), 1.85-1.78 (m, 1H), 1.05 (d, J=6.9 Hz, 3H),0.96-0.87 (m, 1H). Analytical HPLC (Method A): RT=9.26 min,purity=99.7%; Factor XIa Ki=0.1 nM, Plasma Kallikrein Ki=10 nM.

Example 128 Preparation of(9R,13S)-13-{4-[5-chloro-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(Â²Hâ,f)methyl-9-methyl-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

(9R,13S)-13-{4-[5-Chloro-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(²H₃)methyl-9-methyl-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(1.68 mg, 15% yield) was prepared in a similar manner as the proceduredescribed in Example 167, using(9R,13S)-13-amino-3-(²H₃)methyl-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(5.35 mg, 0.018 mmol), prepared as described in Intermediate 33. MS(ESI)m/z: 598.3 (M+H)⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.17 (s, 1H), 7.86 (s, 1H),7.83 (d, J=2.4 Hz, 1H), 7.75 (s, 1H), 7.68 (dd, J=8.4, 2.4 Hz, 1H),7.59-7.55 (m, 3H), 7.49 (s, 1H), 7.32 (d, J=7.3 Hz, 1H), 6.23 (s, 1H),5.81 (dd, J=13.1, 3.4 Hz, 1H), 2.53-2.26 (m, 2H), 2.13-1.80 (m, 3H),1.63-1.49 (m, 2H), 1.27-1.09 (m, 4H), 1.01-0.91 (m, 2H), 0.78-0.69 (m,2H). Analytical HPLC (Method A): RT=8.15 min, purity=95.3%; Factor XIaKi=2 nM, Plasma Kallikrein Ki=280 nM

Example 129 Preparation of6-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-3-[(9R,13S)-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-3,4-dihydropyrimidin-4-one

6-[3-Chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-3-[(9R,13S)-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-3,4-dihydropyrimidin-4-onewas prepared in a similar manner as the procedure described in Example123 by using(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one,prepared as described in Intermediate 30. ¹H NMR (400 MHz, CD₃OD δ 8.99(s, 1H), 8.73 (d, J=5.3 Hz, 1H), 8.32 (s, 1H), 8.30 (s, 1H), 7.86 (dd,J=8.6, 7.7 Hz, 1H), 7.57 (s, 1H), 7.56-7.52 (m, 2H), 7.49 (d, J=5.1 Hz,1H), 6.61 (s, 1H), 6.18 (dd, J=12.5, 5.1 Hz, 1H), 2.67 (d, J=11.7 Hz,1H), 2.36-2.22 (m, 1H), 2.19-1.99 (m, 3H), 1.82 (br. s., 1H), 1.49 (br.s., 1H), 1.24 (m, 1H), 0.76 (d, J=7.3 Hz, 3H), 0.45 (br. s., 1H).MS(ESI) m/z: 630.2 (M+H)⁺. Analytical HPLC (Method A): RT=11.06 min,purity=99.3%; Factor XIa Ki=0.8 nM, Plasma Kallikrein Ki=880 nM.

Example 130 Preparation of(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaene-16-carbonitrile

To(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaene-16-carboxamide,described in Example 84, (0.004 g, 5.98 μmol) in ACN (0.3 mL), cooled to0° C., was added several drops of pyridine, then POCl₃ (0.91 mg, 5.98μmol). After 2 h, the reaction was concentrated and purified bypreparative LCMS to afford(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaene-16-carboxamide(1.7 mg, 43%) as a white solid. MS(ESI) m/z: 650.3 (M+H)⁺. ¹H NMR (500MHz, DMSO-d₆) δ 9.39 (s, 1H), 8.71 (s, 1H), 8.56 (s, 1H), 7.95 (d, J=1.4Hz, 2H), 7.89 (t, J=2.9 Hz, 3H), 7.87-7.80 (m, 2H), 7.77-7.71 (m, 1H),6.40 (s, 1H), 5.55 (d, J=10.5 Hz, 1H), 1.98-1.79 (m, 2H), 1.52-1.36 (m,1H), 1.12 (br. s., 1H), 1.04-0.98 (m, 1H), 0.96 (d, J=6.9 Hz, 3H).Analytical HPLC (Method C) RT=1.76 min., purity=99%; Factor XIa Ki=0.2nM, Plasma Kallikrein Ki=29 nM.

Example 131 Preparation of(9R,13S)-13-(4-{5-chloro-2-[4-(trimethylsilyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate

131A. Preparation of6-{5-chloro-2-[4-(trimethylsilyl)-1H-1,2,3-triazol-1-yl]phenyl}pyrimidin-4-ol,hydrobromide

A clear, yellow solution of4-{5-chloro-2-[4-(trimethylsilyl-1H-1,2,3-triazol-1-yl]phenyl}-6-methoxypyrimidine(0.027 g, 0.075 mmol), prepared as described in Intermediate 9, in AcOH(0.75 ml) and 48% aq HBr (0.42 ml, 3.75 mmol) was warmed to 65° C. After1.5 h, the reaction was concentrated. MeOH was added and the reactionmixture concentrated. This was repeated (2×) to give an 86:14 mixture6-{5-chloro-2-[4-(trimethylsilyl)-1H-1,2,3-triazol-1-yl]phenyl}pyrimidin-4-ol,hydrobromide and6-[5-chloro-2-(1H-1,2,3-triazol-1-yl)phenyl]pyrimidin-4-ol, hydrobromide(0.0294 g, 92% yield) as an off-white solid. MS(ESI) m/z: 346.0 (M+H)⁺.

131B. Preparation of(9R,13S)-13-(4-{5-chloro-2-[4-(trimethylsilyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate

(9R,13S)-13-(4-{5-Chloro-2-[4-(trimethylsilyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate (0.0087 g, 16% yield) was prepared in a similar manneras the procedure described in Example 128, by using6-{5-chloro-2-[4-(trimethylsilyl)-1H-1,2,3-triazol-1-yl]phenyl}pyrimidin-4-olhydrobromide and(9R,13S)-13-amino-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one,prepared as described in Intermediate 32. MS(ESI) m/z: 628.4 (M+H)⁺ and630.5 (M+2+H)⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.84 (s, 1H), 8.71 (d, J=5.1Hz, 1H), 8.17 (s, 1H), 7.88 (d, J=2.4 Hz, 1H), 7.72 (dd, J=8.6, 2.4 Hz,1H), 7.66 (s, 1H), 7.63 (d, J=8.4 Hz, 1H), 7.51 (dd, J=5.2, 1.4 Hz, 1H),7.48 (s, 1H), 6.13 (s, 1H), 5.98 (dd, J=12.7, 4.3 Hz, 1H), 4.04 (s, 3H),2.74-2.66 (m, 1H), 2.32-2.21 (m, 1H), 2.12-1.90 (m, 2H), 1.66-1.53 (m,1H), 1.53-1.39 (m, 1H), 0.99 (d, J=7.0 Hz, 3H), 0.73-0.58 (m, 1H), 0.29(m, 9H). ¹⁹F NMR (376 MHz, CD₃OD) δ −77.51 (br. s., 1F). Analytical HPLC(Method X): RT=6.62 min, purity=93.5%; Factor XIa Ki=29 nM, PlasmaKallikrein Ki=760 nM.

Example 132 Preparation of(9R,13S)-13-[4-(3-chloro-2,6-difluorophenyl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate

To a 1-dram vial containing a white suspension of6-(3-chloro-2,6-difluorophenyl) pyrimidin-4-ol (0.013 g, 0.054 mmol),prepared as described in Intermediate 4, and HATU (0.027 g, 0.070 mmol)in ACN (0.54 ml) was added DBU (0.012 ml, 0.081 mmol). The resultingbright yellow solution was stirred at rt for 20 min. Over time thissolution became a dull yellow-orange color. Then a clear, brown solutionof(9R,13S)-13-amino-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one,2 HCl (0.020 g, 0.054 mmol), prepared as described in Intermediate 32,and DBU (0.016 ml, 0.107 mmol) in DMF (0.54 ml) was added. After 2.5 h,the reaction was stopped. Purification by reverse phase chromatographygave(9R,13S)-13-[4-(3-chloro-2,6-difluorophenyl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate (0.0152 g, 43% yield) as an off-white solid. MS(ESI)m/z: 525.1 (M+H)⁺. ¹H NMR (500 MHz, CD₃OD) δ 9.04 (s, 1H), 8.75 (d,J=5.0 Hz, 1H), 7.73 (s, 1H), 7.63 (ddd, J=9.1, 8.3, 5.5 Hz, 1H),7.55-7.51 (m, 1H), 7.50 (s, 1H), 7.14 (td, J=9.1, 1.7 Hz, 1H), 6.66 (d,J=0.6 Hz, 1H), 6.10-6.02 (m, 1H), 4.05 (s, 3H), 2.76-2.68 (m, 1H), 2.37(tt, J=12.8, 4.5 Hz, 1H), 2.15-2.04 (m, 2H), 1.68-1.58 (m, 1H),1.56-1.45 (m, 1H), 1.02 (d, J=6.9 Hz, 3H), 0.80-0.65 (m, 1H). ¹⁹F NMR(471 MHz, CD₃OD) δ −77.53 (s), −114.79 (d, J=4.3 Hz), −115.50 (d, J=4.3Hz). Analytical HPLC (Method A): RT=7.37 min, purity=99.7%; Factor XIaKi=33 nM, Plasma Kallikrein Ki=290 nM.

Example 133 Preparation of(9R,13S)-13-{4-[5-chloro-2-(1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate

(9R,13S)-13-{4-[5-Chloro-2-(1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate (14 mg, 38% yield) was prepared in a similar manner asthe procedure described in Example 132, by replacing6-(3-chloro-2,6-difluorophenyl)pyrimidin-4-ol with6-[5-chloro-2-(1H-1,2,3-triazol-1-yl)phenyl]pyrimidin-4-ol (0.015 g,0.054 mmol), prepared as described in Intermediate 8. MS(ESI) m/z: 558.4(M+H)⁺. ¹H NMR (500 MHz, CD₃OD) δ 8.83 (s, 1H), 8.71 (d, J=5.0 Hz, 1H),8.21 (s, 1H), 7.89 (d, J=2.2 Hz, 1H), 7.84 (br. s., 1H), 7.72 (dd,J=8.4, 2.3 Hz, 1H), 7.67 (s, 1H), 7.62 (d, J=8.5 Hz, 1H), 7.51 (dd,J=5.1, 1.5 Hz, 1H), 7.48 (s, 1H), 6.18 (s, 1H), 6.00-5.93 (m, 1H), 4.04(s, 3H), 2.73-2.66 (m, 1H), 2.31-2.23 (m, 1H), 2.11-1.91 (m, 2H),1.64-1.54 (m, 1H), 1.51-1.40 (m, 1H), 1.00 (d, J=6.9 Hz, 3H), 0.72-0.59(m, 1H). ¹⁹F NMR (471 MHz, CD₃OD) δ −77.37 (s). Analytical HPLC (MethodA): RT=6.22 min, purity=99.2%; Factor XIa Ki=1.8 nM, Plasma KallikreinKi=110 nM.

Example 134 Preparation of(13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate

134A. Preparation of tert-butylN-[(1S)-1-{4-[4-(but-3-enamido)-1-(difluoromethyl)-1H-pyrazol-5-yl]pyridin-2-yl)}but-3-en-1-yl]carbamate

To a cooled (−5° C.) yellow solution of tert-butylN-[(1S)-1-{4-[4-amino-1-(difluoromethyl)-1H-pyrazol-5-yl]pyridin-2-yl}but-3-en-1-yl]carbamate(0.608 g, 1.60 mmol), prepared as described in Intermediate 30C, inEtOAc (10.1 ml) was added but-3-enoic acid (0.14 ml, 1.60 mmol) andpyridine (0.26 ml, 3.21 mmol). Next, T3P® (50% in EtOAc, 1.43 ml, 2.40mmol) was added dropwise. The resulting orange solution was allowed towarm to rt. After 2 h, the reaction was diluted with EtOAc and washedwith sat NaHCO₃, brine, dried over Na₂SO₄, filtered and concentrated togive a yellow foam weighing 0.702 g. Purification by normal phasechromatography gave tert-butylN-[(1S)-1-{4-[4-(but-3-enamido)-1-(difluoromethyl)-1H-pyrazol-5-yl]pyridin-2-yl}but-3-en-1-yl]carbamate(0.374 g, 52% yield) as a white foam. MS(ESI) m/z: 448.2 (M+H)⁺. ¹H NMR(500 MHz, CD₃OD) δ 8.65 (d, J=4.7 Hz, 1H), 8.04 (s, 1H), 7.44 (s, 1H),7.40 (t, J=58.0 Hz, 1H), 7.36 (d, J=4.4 Hz, 1H), 5.92 (ddt, J=17.1,10.2, 7.0 Hz, 1H), 5.80 (ddt, J=17.2, 10.2, 6.9 Hz, 1H), 5.19-5.13 (m,2H), 5.12-5.03 (m, 2H), 4.81-4.75 (m, 1H), 3.08 (d, J=6.9 Hz, 2H),2.67-2.59 (m, 1H), 2.54-2.46 (m, 1H), 1.42 (s, 9H). ¹⁹F NMR (471 MHz,CD₃OD) δ −93.82 (br. s).

134B. Preparation of tert-butylN-[(10E,13S)-3-(difluoromethyl)-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate

A solution of tert-butylN-[(1S)-1-{4-[4-(but-3-enamido)-1-(difluoromethyl)-1H-pyrazol-5-yl]pyridin-2-yl}but-3-en-1-yl]carbamate(0.374 g, 0.836 mmol) in DCE (20.89 ml) was purged with Ar (3×). To thereaction mixture was added Second Generation Grubbs Catalyst (0.284 g,0.334 mmol). The microwave vial was sealed and the reaction was heatedin a microwave at 115° C. for 1 h. The reaction was cooled to rt andconcentrated. The residue was purified by normal phase chromatography togive tert-butylN-[(10E,13S)-3-(difluoromethyl)-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate(0.106 g, 30% yield) as a brown residue. MS(ESI) m/z: 420.1 (M+H)⁺.

134C. Preparation of tert-butylN-[(13S)-3-(difluoromethyl)-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate

A clear, orange-brown solution of tert-butylN-[(10E,13S)-3-(difluoromethyl)-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate(0.105 g, 0.250 mmol) in EtOH (5.0 ml) was purged with Ar for severalmin. Next, 10% Pd/C (0.027 g, 0.025 mmol) was added and the suspensionwas pressurized with H₂ gas to 55 psi. After 17 h, CELITE® was added.The reaction was filtered through a nylon filter, eluting with EtOH togive a clear, orange solution. The filtrate was concentrated to give aclear, orange residue. Purification by reverse phase chromatographygave, after neutralization of the fractions with sat NaHCO₃ andconcentration, a white solid. The solid was partitioned between EtOAcand water, and the layers were separated. The aqueous layer wasextracted with EtOAc. The organic layers were combined and washed withbrine, dried over Na₂SO₄, filtered and concentrated to give tert-butylN-[(13S)-3-(difluoromethyl)-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate(0.0518 g, 49% yield) as a white solid. MS(ESI) m/z: 422.1 (M+H)⁺.

134D. Preparation of(13S)-13-amino-3-(difluoromethyl)-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one,bis-hydrochloride

A clear, colorless solution of tert-butylN-[(13S)-3-(difluoromethyl)-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate(0.0518 g, 0.123 mmol) in 4 M HCl in dioxane (1.54 ml, 6.15 mmol) wasstirred at rt. After 5 min, a white precipitate formed. After 1 h, thereaction was concentrated to give(13S)-13-amino-3-(difluoromethyl)-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one,bis-hydrochloride (0.0503 g, 104% yield) as an off-white solid. MS(ESI)m/z: 322.1 (M+H)⁺. ¹H NMR (500 MHz, CD₃OD) δ 8.82 (d, J=5.2 Hz, 1H),7.72 (s, 1H), 7.59 (dd, J=60.0, 57.2 Hz, 1H), 7.58 (d, J=5.2 Hz, 1H),7.54 (s, 1H), 4.61 (dd, J=11.1, 5.1 Hz, 1H), 2.45 (ddd, J=12.6, 7.4, 2.3Hz, 1H), 2.22-2.13 (m, 1H), 2.06-1.99 (m, 1H), 1.87-1.71 (m, 2H),1.67-1.57 (m, 1H), 1.52-1.42 (m, 1H), 0.84-0.73 (m, 1H). ¹⁹F NMR (471MHz, CD₃OD) δ −89.17 (d, J=228.9 Hz, 1F), −98.00 (d, J=227.5 Hz, 1F).

134E. Preparation of(13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate

To a 1-dram vial containing a yellow suspension of6-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol(0.016 g, 0.051 mmol), prepared as described in Intermediate 9, and HATU(0.025 g, 0.066 mmol) in ACN (0.51 ml) was added DBU (0.011 ml, 0.076mmol). The resulting yellow-orange solution was stirred at rt for 20min. Over time the solution became a dull yellow-orange color. Then aclear, yellow solution of(13S)-13-amino-3-(difluoromethyl)-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one,bis-hydrochloride (0.020 g, 0.051 mmol) and DBU (0.015 ml, 0.101 mmol)in DMF (0.51 ml) were added. The reaction was stirred at rt. After 3 h,the reaction was quenched with sat NH₄Cl. The mixture was partitionedbetween EtOAc and water and the layers were separated. The aqueous layerwas extracted with EtOAc (2×). The organic layers were combined andwashed with sat NaHCO₃, brine, dried over Na₂SO₄, filtered andconcentrated to give a clear, yellow residue weighing 0.040 g.Purification by reverse phase chromatography gave(13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate (0.0175 g, 47% yield) as a white solid. MS(ESI) m/z:612.2 (M+H)⁺ and 614.1 (M+2+H)⁺. ¹H NMR (500 MHz, DMSO-d6, 60° C.) δ9.28 (s, 1H), 8.78 (d, J=0.5 Hz, 1H), 8.72 (d, J=5.0 Hz, 1H), 8.64 (s,1H), 7.91 (d, J=2.2 Hz, 1H), 7.89 (t, J=57.8 Hz, 1H), 7.86 (s, 1H),7.81-7.78 (m, 1H), 7.72 (d, J=8.5 Hz, 1H), 7.64 (d, J=0.6 Hz, 1H), 7.42(dd, J=5.1, 1.2 Hz, 1H), 6.32 (d, J=0.8 Hz, 1H), 5.93 (dd, J=12.7, 4.4Hz, 1H), 2.41-2.36 (m, 1H), 2.29-2.20 (m, 1H), 2.00-1.87 (m, 3H),1.64-1.53 (m, 1H), 1.44-1.33 (m, 1H), 0.76-0.66 (m, 1H). ¹⁹F NMR (471MHz, DMSO-d₆) δ −73.75 (br. s), −90.34 (d, J=227.4 Hz), −95.01 (d,J=228.9 Hz). Analytical HPLC (Method A): RT=7.78 min, purity=99.8%.

Example 135 Preparation of(9S,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

135A. Preparation of tert-butyl((1S)-1-(4-(1-(difluoromethyl)-4-(2-methylbut-3-enamido)-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate

To a N₂ flushed, 3-necked, 250 mL RBF was added a solution of(S)-tert-butyl(1-(4-(4-amino-1-(difluoromethyl)-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate(1.8 g, 4.74 mmol), prepared as described in Intermediate 30C, and EtOAc(20 mL). The solution was cooled to −10° C. and (±)-2-methylbut-3-enoicacid (0.475 g, 4.74 mmol), pyridine (0.767 mL, 9.49 mmol), and T3P®(4.24 mL, 7.12 mmol) were added. The cooling bath was removed and thesolution was allowed to warm to rt and then stir over a period of 20 h.Water (15 mL) and EtOAc (15 mL) were added and the mixture was stirredfor 30 min. The organic phase was separated and the aqueous layer wasextracted with EtOAc (30 mL). The combined organic extracts were washedwith brine (50 mL), dried over Na₂SO₄, filtered and concentrated.Purification by normal phase chromatography eluting with a gradient ofhexanes/EtOAc gave racemic tert-butyl((1S)-1-(4-(1-(difluoromethyl)-4-(2-methylbut-3-enamido)-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate(1.7 g, 3.50 mmol, 74% yield). MS(ESI) m/z: 462.4 [M+H]+.

135B1. Preparation of tert-butylN-[(9R,10E,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0²,⁶]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate,and 135B2. tert-ButylN-[(9S,10E,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate

To a N₂ flushed, 500 mL, 3-necked, RBF was added a solution oftert-butyl((1S)-1-(4-(1-(difluoromethyl)-4-(2-methylbut-3-enamido)-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate(1.7 g, 3.68 mmol) in EtOAc (175 mL). The solution was sparged with Arfor 15 min. Second Generation Grubbs Catalyst (0.782 g, 0.921 mmol) wasadded in one portion. The reaction mixture was heated to reflux for 24h. After cooling to rt, the solvent was removed and the residue waspurified by normal phase chromatography eluting with a gradient ofDCM/MeOH to yield (separated the diastereomers) tert-butylN-[(9R,10E,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0²,⁶]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate(0.33 g, 0.75 mmol, 20% yield) and tert-butylN-[(9S,10E,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate(0.34 g, 0.77 mmol, 21% yield) as a tan solid. Both diastereomers:MS(ESI) m/z: 434.3 [M+H]⁺.

135C. Preparation of tert-butylN-[(9S,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate

Pd/C (0.082 g, 0.078 mmol) was added to a 100 mL Parr hydrogenationflask containing a solution of tert-butylN-[(9S,10E,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0²,⁶]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate(0.33 g, 0.775 mmol) in EtOH (15 mL). The flask was purged with N₂ andpressurized to 55 psi of H₂ and allowed to stir for 5 h. The reactionwas filtered through CELITE® and concentrated to yield tert-butylN-[(9S,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate(0.3 g, 0.654 mmol, 84% yield) as a tan solid. MS(ESI) m/z: 436.3[M+H]⁺.

135D. Preparation of(9S,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

4 N HCl in dioxane (5.00 mL, 20.0 mmol) was added to a solution oftert-butylN-[(9S,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate(0.300 g, 0.689 mmol) in MeOH (5 mL). The reaction was allowed to stirat rt for 1 h. The reaction was concentrated to yield(9S,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onebis-hydrochloride (0.24 g, 0.644 mmol, 93% yield) as a brown solid whichwas then dissolved in MeOH (1 mL) to give a clear, brown solution. Thesolution was added to a pre-rinsed AGILENT® StratoSpheres SPE PL-HCO₃ MPResin cartridge. Gravity filtration, eluting with MeOH, gave a clear,slightly yellow filtrate. Concentration provided(9S,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(0.18 g, 94%) as a pale yellow solid. MS(ESI) m/z: 336.3 [M+H]⁺.

135E. Preparation of(9S,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate

(9S,13S)-13-{4-[5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate was prepared in a similar manner as the proceduresdescribed in Example 56, by using6-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol(0.221 g, 0.716 mmol), prepared as described in Intermediate 9, and(9S,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(0.021 g, 0.062 mmol) to yield(9S,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate (0.16 g, 0.205 mmol, 29% yield). ¹H NMR (400 MHz,CD₃OD) δ 8.85 (s, 1H), 8.75 (d, J=5.1 Hz, 1H), 8.37 (s, 1H), 7.93 (d,J=2.2 Hz, 1H), 7.85-7.75 (m, 3H), 7.72-7.67 (m, 1H), 7.62 (s, 1H),7.57-7.48 (m, 1H), 6.43 (s, 1H), 6.08 (dd, J=12.9, 4.3 Hz, 1H),2.41-2.30 (m, 1H), 2.29-2.17 (m, 1H), 2.09-1.90 (m, 2H), 1.68-1.52 (m,2H), 1.28 (d, J=6.8 Hz, 3H), 0.93-0.81 (m, 1H). MS(ESI) m/z: 626.3[M+H]⁺. Analytical HPLC (Method A): RT=9.03 min, purity=>95.0%; FactorXIa Ki=1.7 nM, Plasma Kallikrein Ki=35 nM.

Example 136 Preparation of(9R,13S)-13-{4-[5-chloro-2-(4-methyl-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate

136A. Preparation of4-[5-chloro-2-(4-methyl-1H-1,2,3-triazol-1-yl)phenyl]-6-methoxypyrimidinetrifluoroacetate

To a cooled (0° C.), clear, yellow solution of4-chloro-2-(6-methoxypyrimidin-4-yl)aniline (0.095 g, 0.403 mmol),prepared as described in Intermediate 8A, in EtOH (5.0 ml) was addedHunig's base (0.42 ml, 2.42 mmol). After 10 min, a suspension ofN′—[(2E)-1,1-dichloropropan-2-ylidene]-4-methylbenzene-1-sulfonohydrazide(0.242 g, 0.52 mmol) in ACN (3.3 ml) was added dropwise. The resultingorange solution was allowed to warm to rt. After 23 h, the reaction wasstopped and concentrated to give a dark brown oil. Purification byreverse phase chromatography gave, after concentration,4-[5-chloro-2-(4-methyl-1H-1,2,3-triazol-1-yl)phenyl]-6-methoxypyrimidinetrifluoroacetate (0.0499 g, 30% yield) as a clear, yellow oil. MS(ESI)m/z: 302.1 (M+H)⁺. 1H NMR (500 MHz, CD₃OD) δ 8.64 (d, J=1.1 Hz, 1H),7.88 (d, J=0.8 Hz, 1H), 7.85 (d, J=2.2 Hz, 1H), 7.73 (dd, J=8.5, 2.2 Hz,1H), 7.62 (d, J=8.5 Hz, 1H), 6.59 (d, J=1.1 Hz, 1H), 3.97 (s, 3H), 2.33(d, J=0.8 Hz, 3H).

136B. Preparation of6-[5-chloro-2-(4-methyl-1H-1,2,3-triazol-1-yl)phenyl]pyrimidin-4-ol

A clear, yellow solution of4-(5-chloro-2-(4-methyl-1H-1,2,3-triazol-1-yl)phenyl)-6-methoxypyrimidine,TFA (0.0499 g, 0.12 mmol) in AcOH (1.20 ml) and 48% aq HBr (0.68 ml,6.00 mmol) was warmed to 85° C. After 1 h, the reaction was cooled to rtand then was concentrated to give a yellow solid. The yellow solid wassuspended in EtOAc and sat NaHCO₃ was added. The layers were separatedand the aqueous layer was extracted with EtOAc (2×). The organic layerswere combined and washed with brine, dried over Na₂SO₄, filtered andconcentrated to give an off-white solid weighing 0.032 g. The solid wassuspended in EtOAc (1 mL) and sonicated. The solid was collected byfiltration, rinsed with EtOAc, air-dried, and dried under vacuum to give6-[5-chloro-2-(4-methyl-1H-1,2,3-triazol-1-yl)phenyl]pyrimidin-4-ol(0.0144 g, 40% yield) as an off-white solid. MS(ESI) m/z: 288.1 (M+H)⁺.¹H NMR (500 MHz, CD₃OD) δ 8.07 (s, 1H), 7.92 (s, 1H), 7.84 (d, J=2.2 Hz,1H), 7.71 (dd, J=8.5, 2.5 Hz, 1H), 7.60 (d, J=8.5 Hz, 1H), 6.22 (s, 1H),2.36 (s, 3H).

136C. Preparation of(9R,13S)-13-{4-[5-chloro-2-(4-methyl-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate

(9R,13S)-13-{4-[5-Chloro-2-(4-methyl-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate (0.0070 g, 32% yield) was prepared in a similar manneras the procedure described in Example 56, by using6-[5-chloro-2-(4-methyl-1H-1,2,3-triazol-1-yl)phenyl]pyrimidin-4-ol and(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one,prepared in Intermediate 30. MS(ESI) m/z: 606.3 (M+H)⁺ and 608.2(M+2+H)⁺. ¹H NMR (500 MHz, CD₃OD) δ 8.91 (s, 1H), 8.73 (d, J=5.2 Hz,1H), 7.91 (d, J=0.8 Hz, 1H), 7.88 (d, J=2.5 Hz, 1H), 7.73 (s, 1H), 7.70(dd, J=8.5, 2.5 Hz, 1H), 7.68-7.67 (m, 1H), 7.65 (t, J=60.0 Hz, 1H),7.59 (d, J=8.5 Hz, 1H), 7.53-7.51 (m, 1H), 6.18 (d, J=0.8 Hz, 1H),6.02-5.97 (m, 1H), 2.74-2.66 (m, 1H), 2.35-2.24 (m, 4H), 2.08-1.94 (m,2H), 1.63-1.53 (m, 1H), 1.53-1.42 (m, 1H), 0.99 (d, J=6.9 Hz, 3H),0.67-0.52 (m, 1H). ¹⁹F NMR (471 MHz, CD₃OD) δ −74.24 (s), −75.74 (s),−77.66 (s). Analytical HPLC (Method A): RT=7.55 min, purity=99.8%;Factor XIa Ki=2.2 nM, Plasma Kallikrein Ki=630 nM.

Example 137 Preparation of(9R,13S)-3-(difluoromethyl)-9-methyl-13-(4-{5-methyl-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

(9R,13S)-3-(Difluoromethyl)-9-methyl-13-(4-{5-methyl-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate (11 mg, 24%) was prepared in a similar manner asExample 56 using6-(5-methyl-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol,prepared as described in Example 119D and

(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one,prepared as described in Intermediate 30. MS(ESI) m/z: 640.2 (M+H)⁺. ¹HNMR (400 MHz, CD₃OD) d 8.85-8.74 (m, 3H), 7.84-7.67 (m, 4H), 7.59-7.53(m, 3H), 6.47 (s, 1H), 6.05 (dd, J=12.8, 4.4 Hz, 1H), 2.75 (dd, J=6.7,3.0 Hz, 1H), 2.56 (s, 3H), 2.35-2.27 (m, 1H), 2.10-1.99 (m, 2H),1.64-1.50 (m, 2H), 1.03 (d, J=6.8 Hz, 3H), 0.65 (br. s., 1H) AnalyticalHPLC (Method A): RT=8.85 min, purity=99%; Factor XIa Ki=0.32 nM, PlasmaKallikrein Ki=132 nM.

Example 138 Preparation of(9R,13S)-13-[4-(2-bromo-5-chlorophenyl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

(9R,13S)-13-[4-(2-Bromo-5-chlorophenyl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate (160 mg, 46.8% yield) was prepared in a similar manneras the procedure described in Example 56, by replacing6-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}pyrimidin-4-ol(22.8 mg, 0.067 mmol), prepared as described in Intermediate 15, with6-(2-bromo-5-chlorophenyl)pyrimidin-4-ol (143 mg, 0.501 mmol), preparedas described in Intermediate 44. MS(ESI) m/z: 567.1 (M+H)⁺. ¹H NMR (400MHz, CD₃OD) δ 9.04 (s, 1H), 8.75 (d, J=5.3 Hz, 1H), 7.76 (s, 1H), 7.70(d, J=8.6 Hz, 1H), 7.61-7.54 (m, 2H), 7.50 (s, 1H), 7.38 (dd, J=8.6, 2.4Hz, 1H), 6.70 (s, 1H), 6.05 (dd, J=12.5, 4.0 Hz, 1H), 4.05 (s, 3H),2.78-2.66 (m, 1H), 2.44-2.33 (m, 1H), 2.16-2.03 (m, 2H), 1.70-1.43 (m,2H), 1.02 (d, J=6.8 Hz, 3H), 0.82-0.66 (m, 1H). Analytical HPLC (MethodA): RT=8.45 min, 99.9% purity; Factor XIa Ki=23 nM, Plasma KallikreinKi=420 nM.

Example 139 Preparation of(9R,13S)-13-{4-[3-chloro-2-fluoro-6-(4-methyl-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

(9R,13S)-13-{4-[3-Chloro-2-fluoro-6-(4-methyl-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(0.0174 g, 62% yield) was prepared in a similar manner as the proceduredescribed in Example 56, by using6-[3-chloro-2-fluoro-6-(4-methyl-1H-1,2,3-triazol-1-yl)phenyl]pyrimidin-4-ol,prepared in Example 137B, and(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one, prepared as described in Intermediate 30.MS(ESI) m/z: 624.3 (M+H)⁺ and 626.2 (M+2+H)⁺. ¹H NMR (500 MHz, CD₃OD) δ9.52 (s, 1H), 8.90 (s, 1H), 8.75 (d, J=5.2 Hz, 1H), 7.89 (d, J=0.8 Hz,1H), 7.82 (dd, J=8.7, 7.6 Hz, 1H), 7.74 (d, J=0.8 Hz, 1H), 7.69 (br. s,1H), 7.65 (t, J=58.0 Hz, 1H), 7.53-7.49 (m, 2H), 6.52 (s, 1H), 6.05-5.99(m, 1H), 2.77-2.66 (m, 1H), 2.34-2.23 (m, 4H), 2.09-1.95 (m, 2H),1.64-1.53 (m, 1H), 1.53-1.42 (m, 1H), 0.99 (d, J=7.2 Hz, 3H), 0.69-0.53(m, 1H). ¹⁹F NMR (471 MHz, CD₃OD) δ −74.25 (s), −75.75 (s), −115.22 (s).Analytical HPLC (Method A): RT=7.54 min, purity=99.8%; Factor XIaKi=0.63 nM, Plasma Kallikrein Ki=119 nM.

Example 140 Preparation of(9R,13S)-13-(4-{5-chloro-2-[1-(difluoromethyl)-1H-pyrazol-4-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

140A. Preparation of4-(5-chloro-2-(1-(difluoromethyl)-1H-pyrazol-4-yl)phenyl)-6-methoxypyrimidine

To a sealable vial was added4-(2-bromo-5-chlorophenyl)-6-methoxypyrimidine (0.08 g, 0.267 mmol),1-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(0.072 g, 0.294 mmol), 3 M aq KH₂PO₄ (0.27 ml, 0.81 mmol) and THF (2.67ml). Ar was bubbled through the reaction mixture for several min and(DtBPF)PdCl₂ (8.70 mg, 0.013 mmol) was added. The vial was sealed andheated at 90° C. for 15 h. The reaction was cooled to rt, diluted withEtOAc, washed with brine, dried over Na₂SO₄, filtered, and concentrated.Purification by normal phase chromatography afforded4-(5-chloro-2-(1-(difluoromethyl)-1H-pyrazol-4-yl)phenyl)-6-methoxypyrimidine(0.05 g, 56% yield) as a white solid. MS(ESI) m/z: 337.2 (M+H)⁺. ¹H NMR(400 MHz, CDCl₃) δ 8.81 (d, J=0.9 Hz, 1H), 7.69 (s, 1H), 7.54 (d, J=2.2Hz, 1H), 7.48-7.43 (m, 1H), 7.41-7.35 (m, 2H), 7.17 (t, J=54.0 Hz, 1H),6.61 (d, J=1.1 Hz, 1H), 3.99 (s, 3H).

140B. Preparation of6-(5-chloro-2-(1-(difluoromethyl)-1H-pyrazol-4-yl)phenyl) pyrimidin-4-ol

A clear solution of4-(5-chloro-2-(1-(difluoromethyl)-1H-pyrazol-4-yl)phenyl)-6-methoxypyrimidine(0.05 g, 0.148 mmol) in HOAc (0.742 ml) and 48% aq HBr (0.84 ml, 7.42mmol) was warmed to 65° C. After 3 h, the reaction was cooled to rt andconcentrated. The residue was dissolved in EtOAc, washed with satNaHCO₃, brine, dried over Na₂SO₄, filtered, and concentrated. Et₂O (3ml) was added and the mixture was sonicated. The solid was collected byfiltration and rinsed with Et₂O (2 ml), air-dried to give6-(5-chloro-2-(1-(difluoromethyl)-1H-pyrazol-4-yl)phenyl)pyrimidin-4-ol(0.03 g, 63% yield) as a white solid. MS(ESI) m/z: 323.2 (M+H)⁺. ¹H NMR(400 MHz, CD₃OD) δ 8.20 (d, J=1.1 Hz, 1H), 8.05 (s, 1H), 7.61-7.27 (m,5H), 6.40 (d, J=1.1 Hz, 1H).

140C. Preparation of(9R,13S)-13-(4-{5-chloro-2-[1-(difluoromethyl)-1H-pyrazol-4-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate

(9R,13S)-13-(4-{5-Chloro-2-[1-(difluoromethyl)-1H-pyrazol-4-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate (10 mg, 32% yield) was prepared in a similar manner asthe procedure described in Example 56, by using6-(5-chloro-2-(1-(difluoromethyl)-1H-pyrazol-4-yl)phenyl)pyrimidin-4-ol(14.01 mg, 0.043 mmol). MS(ESI) m/z: 605.2 (M+H)⁺. ¹H NMR (400 MHz,CD₃OD) δ 8.95 (s, 1H), 8.74 (d, J=5.3 Hz, 1H), 8.04 (s, 1H), 7.72 (s,1H), 7.60-7.25 (m, 7H), 6.42 (s, 1H), 6.02 (dd, J=12.7, 4.3 Hz, 1H),4.05 (s, 3H), 2.76-2.66 (m, 1H), 2.39-2.27 (m, 1H), 2.14-1.99 (m, 2H),1.67-1.42 (m, 2H), 1.02 (d, J=6.8 Hz, 3H), 0.81-0.65 (m, 1H). AnalyticalHPLC (Method A): RT=8.18 min, 98.5% purity; Factor XIa Ki=9 nM, PlasmaKallikrein Ki=910 nM.

Example 141 Preparation of(9R,13S)-13-[4-(3-fluoro-4-methylpyridin-2-yl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

141A. Preparation of 4-methoxy-6-(tributylstannyl)pyrimidine

To a RBF was added 4-chloro-6-methoxypyrimidine (3.15 g, 21.79 mmol),1,1,1,2,2,2-hexabutyldistannane (10.92 mL, 21.79 mmol), toluene (50 mL)and Pd(PPh₃)₄ (1.259 g, 1.090 mmol). The reaction was purged with Ar andthen stirred at 120° C. overnight. The reaction was then partitionedbetween EtOAc (30 ml) and water (25 ml). The organic layer wasseparated, washed with sat NaCl (20 ml), dried over MgSO₄, filtered andconcentrated. The crude product was purified using ISCO system (0-30%EtOAc/Hex gradient) to give 4-methoxy-6-(tributylstannyl)pyrimidine (200mg, 0.501 mmol, 2.3% yield) as a clear liquid. ¹H NMR (400 MHz, CDCl₃) δ8.85 (d, J=1.1 Hz, 1H), 6.94 (d, J=1.1 Hz, 1H), 3.97 (s, 3H), 1.60-1.55(m, 6H), 1.36-1.32 (m, 6H), 1.20-1.13 (m, 6H), 0.96-0.91 (m, 9H);MS(ESI) m/z: 401.1 (M+H)⁺.

141B. Preparation of4-(3-fluoro-4-methylpyridin-2-yl)-6-methoxypyrimidine trifluoroacetate

To a sealed tube was added 2-bromo-3-fluoro-4-methylpyridine (25.7 mg,0.135 mmol), 4-methoxy-6-(tributylstannyl)pyrimidine (45 mg, 0.113mmol), toluene (1.5 mL) and Pd(PPh₃)₄ (13.03 mg, 0.011 mmol). Thereaction was purged with Ar and then sealed and stirred at 120° C.overnight. The reaction was partitioned between EtOAc (25 ml) and water(20 ml). The organic layer was separated, washed with sat NaCl (10 ml),dried over MgSO₄, filtered and concentrated. The crude product waspurified using prep-HPLC to give4-(3-fluoro-4-methylpyridin-2-yl)-6-methoxypyrimidine trifluoroacetate(20 mg, 0.060 mmol, 53.2% yield) as a purple salt. ¹H NMR (400 MHz,CDCl₃) δ 9.22 (s, 1H), 8.59 (d, J=4.2 Hz, 1H), 7.56 (s, 1H), 7.51 (br.s., 1H), 4.23 (s, 3H), 2.51 (s, 3H); MS(ESI) m/z: 220.1 (M+H)⁺.

141C. Preparation of 6-(3-fluoro-4-methylpyridin-2-yl)pyrimidin-4-ol

To a RBF was added 4-(3-fluoro-4-methylpyridin-2-yl)-6-methoxypyrimidine(20 mg, 0.060 mmol), AcOH (0.5 mL) and HBr (0.34 mL, 3.00 mmol). Thereaction was stirred at 85° C. for 45 min. Then toluene (25 ml) wasadded and the reaction was concentrated. The residue was thenpartitioned between EtOAc (25 ml) and sat NaHCO₃ (25 ml). The organiclayer was separated, washed with water (15 ml) and sat NaCl (15 ml),dried over MgSO₄, filtered and concentrated, to give6-(3-fluoro-4-methylpyridin-2-yl)pyrimidin-4-ol (10 mg, 0.049 mmol, 81%yield) as an oil. MS(ESI) m/z: 206.1 (M+H)⁺.

141D. Preparation of(9R,13S)-13-[4-(3-fluoro-4-methylpyridin-2-yl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate

(9R,13S)-13-[4-(3-Fluoro-4-methylpyridin-2-yl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate (14 mg, 22 μmol, 41.4% yield) was prepared in a similarmanner as the procedure described in Example 56 by using6-(3-fluoro-4-methylpyridin-2-yl)pyrimidin-4-ol (15.3 mg, 0.053 mmol)and(9R,13S)-13-amino-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(16 mg, 0.053 mmol), prepared as described in Intermediate 32. ¹H NMR(400 MHz, CD₃OD) δ 9.21 (br. s., 1H), 8.76 (d, J=4.4 Hz, 1H), 8.49 (br.s., 1H), 7.77 (s, 1H), 7.66 (br. s., 1H), 7.56 (d, J=3.7 Hz, 1H), 7.52(s, 1H), 7.15 (br. s., 1H), 6.10 (d, J=9.9 Hz, 1H), 4.07 (s, 3H), 2.74(d, J=12.3 Hz, 1H), 2.51 (br. s., 3H), 2.40 (br. s., 1H), 2.13 (br. s.,2H), 1.66 (br. s., 1H), 1.54 (br. s., 1H), 1.04 (d, J=6.8 Hz, 3H), 0.75(br. s., 1H); MS(ESI) m/z: 488.2 (M+H)⁺. Analytical HPLC (Method A):RT=6.97 min, purity=97.0%; Factor XIa Ki=110 nM, Plasma KallikreinKi=2,200 nM.

Example 142 Preparation of(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,17-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

(9R,13S)-13-{4-[5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,17-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate (14.2 mg, 24%) was prepared in a similar manner asExample 56, by using6-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]pyrimidin-4-ol,prepared as described in Intermediate 9, and(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,17-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one,prepared as described in Intermediate 37. MS(ESI) m/z: 626.1 (M+H)⁺ and628.1 (M+2+H)⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.62 (d, J=5.1 Hz, 1H),8.35-8.13 (m, 3H), 7.85 (s, 2H), 7.71-7.62 (m, 2H), 7.57-7.53 (m, 1H),7.09-7.03 (m, 1H), 6.36-6.30 (m, 1H), 5.67-5.63 (m, 1H), 2.59-2.54 (m,1H), 2.31-2.24 (m, 1H), 2.04-1.94 (m, 2H), 1.59-1.54 (m, 1H), 1.30-1.21(m, 2H), 1.03 (d, J=6.8 Hz, 3H). Analytical HPLC (Method A): RT=8.54min, purity=99%; Factor XIa Ki=0.4 nM, Plasma Kallikrein Ki=90 nM.

Example 143 Preparation of(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate

(9R,13S)-13-{4-[5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate (9.7 mg, 21% yield) was prepared in a similar manner asthe procedure described in Example 56, by replacing6-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}pyrimidin-4-olwith 6-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]pyrimidin-4-ol(20 mg, 0.065 mmol), prepared as described in Intermediate 9. MS(ESI)m/z: 590.1 (M+H)⁺. ¹H NMR (500 MHz, CD₃OD) δ 8.82 (s, 1H), 8.72 (d,J=5.0 Hz, 1H), 8.33 (s, 1H), 7.88 (d, J=2.5 Hz, 1H), 7.73 (dd, J=8.5,2.2 Hz, 1H), 7.68 (s, 1H), 7.64 (d, J=8.5 Hz, 1H), 7.52-7.49 (m, 1H),7.49 (s, 1H), 6.36 (s, 1H), 5.98 (dd, J=12.5, 3.7 Hz, 1H), 4.04 (s, 3H),2.70 (td, J=6.5, 3.0 Hz, 1H), 2.33-2.24 (m, 1H), 2.12-1.95 (m, 2H),1.65-1.55 (m, 1H), 1.52-1.42 (m, 1H), 1.00 (d, J=6.9 Hz, 3H), 0.74-0.61(m, 1H). Analytical HPLC (Method A): RT=11.54 min, purity=99%; FactorXIa Ki=0.17 nM, Plasma Kallikrein Ki=20 nM.

Example 144 Preparation of(9R,13S)-13-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate

(9R,13S)-13-{4-[3-Chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate (9.9 mg, 22% yield) was prepared in a similar manner asthe procedure described in Example 56, by using6-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]pyrimidin-4-ol(20 mg, 0.061 mmol), prepared as described in Intermediate 10. MS(ESI)m/z: 608.1 (M+H)⁺. ¹H NMR (500 MHz, CD₃OD) δ 8.83 (s, 1H), 8.73 (d,J=5.2 Hz, 1H), 8.32 (s, 1H), 7.85 (dd, J=8.5, 7.7 Hz, 1H), 7.68 (s, 1H),7.55 (dd, J=8.7, 1.5 Hz, 1H), 7.51 (dd, J=5.2, 1.7 Hz, 1H), 7.49 (s,1H), 6.60 (s, 1H), 6.00 (dd, J=12.8, 4.0 Hz, 1H), 4.05 (s, 3H),2.75-2.64 (m, 1H), 2.29 (t, J=12.9 Hz, 1H), 2.14-1.95 (m, 2H), 1.67-1.55(m, 1H), 1.52-1.40 (m, 1H), 1.00 (d, J=6.9 Hz, 3H), 0.67 (m., 1H). ¹⁹FNMR (471 MHz, CD₃OD) δ −76.98 (s), −115.06 (s). Analytical HPLC (MethodA): RT=11.58 min, purity=98.5%; Factor XIa Ki=0.1 nM, Plasma KallikreinKi=6 nM.

Example 145 Preparation of(9R,13S)-13-{4-[2-(4-bromo-1H-1,2,3-triazol-1-yl)-5-chlorophenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate

145A. Preparation of4-[5-chloro-2-(4-bromo-1H-1,2,3-triazol-1-yl)phenyl]-6-methoxypyrimidine

4-[2-(4-Bromo-1H-1,2,3-triazol-1-yl)-5-chlorophenyl]-6-methoxypyrimidine(114 mg, 56.0% yield) was prepared in a similar manner as the proceduredescribed for the preparation of4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-methoxypyrimidine,as described in Intermediate 9D, by replacing NCS with NBS (346 mg,1.945 mmol). MS(ESI) m/z: 368.3 (M+H)⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.69(d, J=0.9 Hz, 1H), 7.75 (d, J=2.4 Hz, 1H), 7.66 (s, 1H), 7.61 (dd,J=8.5, 2.3 Hz, 1H), 7.49 (d, J=8.4 Hz, 1H), 6.52 (d, J=1.1 Hz, 1H), 3.98(s, 3H).

145B. Preparation of6-[2-(4-bromo-1H-1,2,3-triazol-1-yl)-5-chlorophenyl]pyrimidin-4-ol

6-[2-(4-Bromo-1H-1,2,3-triazol-1-yl)-5-chlorophenyl]pyrimidin-4-ol (47mg, 42.9% yield) was prepared in a similar manner as the proceduredescribed in Intermediate 9E, by replacing4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-methoxypyrimidinewith4-[2-(4-bromo-1H-1,2,3-triazol-1-yl)-5-chlorophenyl]-6-methoxypyrimidine(114 mg, 0.311 mmol). MS(ESI) m/z: 354.2 (M+H)⁺. ¹H NMR (400 MHz, CDCl₃)δ 8.01 (s, 1H), 7.76 (s, 1H), 7.73 (d, J=2.2 Hz, 1H), 7.62 (dd, J=8.5,2.1 Hz, 1H), 7.47 (d, J=8.4 Hz, 1H), 6.42 (s, 1H).

145C. Preparation of(9R,13S)-13-{4-[2-(4-bromo-1H-1,2,3-triazol-1-yl)-5-chlorophenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate

(9R,13S)-13-{4-[2-(4-Bromo-1H-1,2,3-triazol-1-yl)-5-chlorophenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate (18.7 mg, 36.3% yield) was prepared in a similar manneras the procedure described in Example 56, by using6-[2-(4-bromo-1H-1,2,3-triazol-1-yl)-5-chlorophenyl]pyrimidin-4-ol (23.6mg, 0.067 mmol). MS(ESI) m/z: 636.3 (M+H)⁺. ¹H NMR (400 MHz, CD₃OD) δ8.80 (s, 1H), 8.73 (d, J=5.3 Hz, 1H), 8.37 (s, 1H), 7.87 (d, J=2.4 Hz,1H), 7.75-7.68 (m, 2H), 7.65-7.60 (m, 1H), 7.53 (dd, J=5.1, 1.5 Hz, 1H),7.49 (s, 1H), 6.35 (s, 1H), 5.97 (dd, J=12.7, 4.3 Hz, 1H), 4.05 (s, 3H),2.75-2.65 (m, 1H), 2.35-2.22 (m, 1H), 2.12-1.95 (m, 2H), 1.66-1.53 (m,1H), 1.51-1.38 (m, 1H), 1.00 (d, J=7.0 Hz, 3H), 0.77-0.60 (m, 1H).Analytical HPLC (Method A): RT=10.12 min, purity=96.9%; Factor XIaKi=0.13 nM, Plasma Kallikrein Ki=18 nM.

Examples 146 and 147 Preparation of1-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)-1H-1,2,3-triazole-4-carboxamidetrifluoroacetate, and1-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)-1H-1,2,3-triazole-4-carbonitriletrifluoro acetate

146A. Preparation of1-[4-chloro-2-(6-methoxypyrimidin-4-yl)phenyl]-1H-1,2,3-triazole-4-carboxamide,and 147A. Preparation of1-[4-chloro-2-(6-methoxypyrimidin-4-yl)phenyl]-1H-1,2,3-triazole-4-carbonitrile

To a suspension of1-[4-chloro-2-(6-methoxypyrimidin-4-yl)phenyl]-1H-1,2,3-triazole-4-carboxamide(150 mg, 0.45 mmol), prepared as described in Intermediate 18A, in DCM(1 mL) was added TFAA (0.3 mL, 2.12 mmol) at rt and the reaction wasstirred for 1 h. The reaction was concentrated to dryness, partitionedbetween sat NaHCO₃ and EtOAc, and the layers were separated. The aqueouslayer was extracted with EtOAc (2×). The combined organic layers wereconcentrated and then purified by normal phase chromatography to give1-(4-chloro-2-(6-methoxypyrimidin-4-yl)phenyl)-1H-1,2,3-triazole-4-carboxamide(80 mg, 53.3% yield). MS(ESI) m/z: 331.3 (M+H)⁺; and1-(4-chloro-2-(6-methoxypyrimidin-4-yl)phenyl)-1H-1,2,3-triazole-4-carboxamide(60.5 mg, 21.3% yield) which were used as is in the next step. MS(ESI)m/z: 331.3.

146B. Preparation of1-[4-chloro-2-(6-hydroxypyrimidin-4-yl)phenyl]-1H-1,2,3-triazole-4-carboxamide,and 147B. Preparation of1-[4-chloro-2-(6-hydroxypyrimidin-4-yl)phenyl]-1H-1,2,3-triazole-4-carbonitrile

To a suspension of a 1:1 mixture of1-(4-chloro-2-(6-methoxypyrimidin-4-yl)phenyl)-1H-1,2,3-triazole-4-carbonitrileand1-(4-chloro-2-(6-methoxypyrimidin-4-yl)phenyl)-1H-1,2,3-triazole-4-carboxamide(60.5 mg, 0.194 mmol) in ACN (1 mL) was added TMSI (12 μL, 0.88 mmol)and the solution was heated at 50° C. overnight. The reaction was pouredinto 10% aq Na₂S₂O₃ s and extracted with EtOAc (3×). The combinedorganic layers were concentrated to dryness then suspended in DCM. Theinsoluble yellow solid was filtered to give a 5:3 mixture of1-[4-chloro-2-(6-hydroxypyrimidin-4-yl)phenyl]-1H-1,2,3-triazole-4-carboxamideand1-[4-chloro-2-(6-hydroxypyrimidin-4-yl)phenyl]-1H-1,2,3-triazole-4-carbonitrile(15 mg) which was used as in is the next step. MS(ESI) m/z: 317.3, 299.3(M+H)⁺. The filtrate was concentrated then purified by normal phasechromatography to give1-[4-chloro-2-(6-hydroxypyrimidin-4-yl)phenyl]-1H-1,2,3-triazole-4-carbonitrile(20 mg, 34.6% yield) as a yellow solid. MS(ESI) m/z: 299.3 ¹H NMR (400MHz, CDCl₃) δ 8.23 (s, 1H), 7.93 (s, 1H), 7.73 (d, J=2.2 Hz, 1H), 7.66(dd, J=8.4, 2.2 Hz, 1H), 7.49 (d, J=8.4 Hz, 1H), 6.54 (s, 1H).

146C. Preparation of1-(4-chloro-2-{1[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)-1H-1,2,3-triazole-4-carboxamidetrifluoroacetate, and 147C. Preparation of1-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)-1H-1,2,3-triazole-4-carbonitriletrifluoroacetate

To a scintillation vial containing a mixture of1-(4-chloro-2-(6-hydroxypyrimidin-4-yl)phenyl)-1H-1,2,3-triazole-4-carbonitrileand1-[4-chloro-2-(6-hydroxypyrimidin-4-yl)phenyl]-1H-1,2,3-triazole-4-carboxamide(15 mg, 0.050 mmol) in ACN (1 mL), was added HATU (24.8 mg, 0.065 mmol)and DBU (11 μL, 0.075 mmol). After 20 min, a solution of(9R,13S)-13-amino-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(18.4 mg, 0.061 mmol), prepared as described in Intermediate 32, in ACN(0.5 ml) and DMF (0.1 ml) was added. The resulting solution was stirredat rt for 2 h then purified by reverse phase chromatography to give twoproducts.1-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)-1H-1,2,3-triazole-4-carboxamidetrifluoroacetate (3.8 mg, 10.5% yield) as a white solid. MS(ESI) m/z:599.4 (M+H)⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.79 (s, 1H), 8.71 (d, J=5.1 Hz,1H), 8.56 (s, 1H), 7.88 (d, J=2.4 Hz, 1H), 7.76-7.71 (m, 1H), 7.69-7.64(m, 2H), 7.51 (dd, J=5.2, 1.4 Hz, 1H), 7.48 (s, 1H), 6.35 (s, 1H), 5.96(dd, J=12.8, 4.2 Hz, 1H), 4.04 (s, 3H), 2.75-2.63 (m, 1H), 2.33-2.21 (m,1H), 2.12-1.92 (m, 2H), 1.66-1.53 (m, 1H), 1.52-1.40 (m, 1H), 1.00 (d,J=6.8 Hz, 3H), 0.74-0.60 (m, 1H). Analytical HPLC (Method A): RT=8.06min, purity=98.4%; Factor XIa Ki=0.44 nM, Plasma Kallikrein Ki=99 nM.

1-(4-Chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)-1H-1,2,3-triazole-4-carbonitriletrifluoroacetate (1.7 mg, 4.9% yield) as a white solid. MS(ESI) m/z:581.3 (M+H)⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.93 (s, 1H), 8.73 (d, J=4.6 Hz,2H), 7.90 (d, J=2.4 Hz, 1H), 7.79-7.73 (m, 1H), 7.71-7.67 (m, 2H), 7.51(dd, J=5.1, 1.5 Hz, 1H), 7.49 (s, 1H), 6.46 (d, J=0.7 Hz, 1H), 5.97 (dd,J=12.7, 4.1 Hz, 1H), 4.05 (s, 3H), 2.70 (m, 1H), 2.34-2.21 (m, 1H),2.13-1.94 (m, 2H), 1.67-1.53 (m, 1H), 1.52-1.39 (m, 1H), 1.01 (d, J=6.8Hz, 3H), 0.71 (m, 1H). Analytical HPLC (Method A): RT=10.08 min,purity=99.2%; Factor XIa Ki=0.11 nM, Plasma Kallikrein Ki=20 nM.

Example 148 Preparation of(10R,14S)-14-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-10-methyl-9-oxo-3,8-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaene-5-carbonitrile

148A. Preparation of tert-butylN-[(10R,14S)-5-bromo-10-methyl-9-oxo-3,8-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-14-yl]carbamate

tert-ButylN-[(10R,14S)-5-bromo-10-methyl-9-oxo-3,8-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-14-yl]carbamate was prepared (0.1 g, 49%yield, dark solid) in a similar manner as Example 81C replacing2-bromo-5-methoxypyridin-3-amine with 2,5-dibromopyridin-3-amine. LCMS(M+H)⁺474-476.08.

148B. Preparation of tert-butylN-[(10R,14S)-5-cyano-10-methyl-9-oxo-3,8-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-14-yl]carbamate

To tert-butylN-[(10R,14S)-5-bromo-10-methyl-9-oxo-3,8-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-14-yl]carbamate(0.1 g, 0.211 mmol) in a microwave tube was added Zn(CN)₂ (0.037 g,0.316 mmol), Zn (4.13 mg, 0.063 mmol) and DMF (2.1 ml). The mixture waspurged with Ar for several min. Pd(t-Bu₃P)₂ (10.77 mg, 0.021 mmol) wasadded. The reaction was sealed and heated at 80° C. for 18 h. Thereaction was partitioned with water (10 ml) and EtOAc (30 ml). Theaqueous layer was extracted with EtOAc (2×10 ml). The combined organiclayers were washed with brine (10 ml), dried (MgSO₄), filtered andconcentrated. The residue was purified normal phase chromatography using100% DCM to 10% MeOH as eluents to give tert-butylN-[(10R,14S)-5-cyano-10-methyl-9-oxo-3,8-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-14-yl]carbamate(20 mg, 22.56% yield). LCMS (M+H)⁺421.3.

148C. Preparation of(10R,14S)-14-amino-10-methyl-9-oxo-3,8-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaene-5-carbonitrile

tert-ButylN-[(10R,14S)-5-cyano-10-methyl-9-oxo-3,8-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-14-yl]carbamate (0.02 g, 0.048 mmol), Example148B, was deprotected and the free-base was produced in a similar manneras Example 81D to afford(10R,14S)-14-amino-10-methyl-9-oxo-3,8-diazatricyclo[13.3.1.0²7]nonadeca-1(19),2(7),3,5,15,17-hexaene-5-carbonitrile (13 mg, 85%) as atan solid. LCMS (M+H)⁺321.3.

148D. Preparation of(10R,14S)-14-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-10-methyl-9-oxo-3,8-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaene-5-carbonitrile

To6-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}pyrimidin-4-ol,described in Intermediate 15, (0.014 g, 0.041 mmol) and HATU (0.020 g,0.053 mmol) in a small vial was added DBU (9.17 μl, 0.061 mmol) in ACN(0.2 mL). After 30 min,(10R,14S)-14-amino-10-methyl-9-oxo-3,8-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaene-5-carbonitrilewas added in DMF (0.4 ml). After 18 h, the reaction was diluted withDMF, filtered and concentrated. The residue was purified by reversephase HPLC using PHENOMENEX® Luna 5U 30×100 mm (10:90 ACN/H₂O to 90:10ACN/H₂O, 0.1% TFA) (20% B start, 14 min gradient) to afford(10R,14S)-14-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-10-methyl-9-oxo-3,8-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaene-5-carbonitrile(4.9 mg, 14%) as a white solid. MS(ESI) m/z: 645.4 (M+H)⁺. ¹H NMR (400MHz, CD₃OD) δ 8.98-8.94 (m, 1H), 8.80 (s, 1H), 8.30-8.24 (m, 1H),8.18-8.13 (m, 1H), 7.96-7.91 (m, 1H), 7.81-7.76 (m, 2H), 7.74-7.68 (m,1H), 7.60 (t, J=7.7 Hz, 1H), 7.32 (s, 1H), 6.49-6.46 (m, 1H), 5.81 (dd,J=12.7, 3.4 Hz, 1H), 2.56 (d, J=7.0 Hz, 1H), 2.31 (d, J=5.1 Hz, 1H),2.16-2.08 (m, 1H), 1.93 (d, J=7.3 Hz, 1H), 1.58 (d, J=7.3 Hz, 1H), 1.46(d, J=6.8 Hz, 1H), 1.37 (br. s., 1H), 1.26-1.21 (m, 1H), 1.17 (s, 3H).Analytical HPLC (Method A) RT=9.37 min, purity=90%; Factor XIa Ki=1.8nM, Plasma Kallikrein Ki=120 nM.

Example 149 Preparation of(9R,13S)-13-(4-{5-chloro-2-[4-({3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy}methyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate

149A. Preparation of4-{5-chloro-2-[4-(fluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-methoxypyrimidine

To a solution of{1-[4-chloro-2-(6-methoxypyrimidin-4-yl)phenyl]-1H-1,2,3-triazol-4-yl}methanol(95 mg, 0.3 mmol), prepared as described in Intermediate 16A, in DCM (6ml) was added DAST (0.040 mL, 0.300 mmol) and the reaction was stirredat rt for 2 h. The reaction was quenched with water, and extracted withDCM. The organic layer was concentrated and purified by normal phasechromatography to give4-{5-chloro-2-[4-(fluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-methoxypyrimidine(56 mg, 0.175 mmol, 58.4% yield) as a clear oil. MS(ESI) m/z: 320.0(M+H)⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.68 (d, J=1.1 Hz, 1H), 7.77 (d, J=2.2Hz, 1H), 7.73 (d, J=2.6 Hz, 1H), 7.64-7.57 (m, 1H), 7.53-7.48 (m, 1H),6.46 (d, J=1.1 Hz, 1H), 5.57 (s, 1H), 5.45 (s, 1H), 3.98-3.87 (m, 3H).¹⁹F NMR (376 MHz, CDCl₃) δ −208.23 (s).

149B. Preparation of6-{2-[4-(bromomethyl)-1H-1,2,3-triazol-1-yl]-5-chlorophenyl}pyrimidin-4-ol

A solution of4-{5-chloro-2-[4-(fluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-methoxypyrimidine(56 mg, 0.175 mmol) in 33% HBr in AcOH (0.5 ml, 4.14 mmol) was heated at85° C. for 1 h. The reaction was concentrated to half the volume then,48% aq HBr (0.2 ml) was added and heated at 85° C. for 1 h. The reactionwas concentrated, and the residue was partitioned between EtOAc and satNaHCO₃. The layers were separated and the aqueous layer was extractedwith EtOAc (2×). The combined organic layers were concentrated andpurified by normal phase chromatography to give6-{2-[4-(bromomethyl)-1H-1,2,3-triazol-1-yl]-5-chlorophenyl}pyrimidin-4-ol.MS(ESI) m/z: 368.2 (M+H)⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.87 (d, J=0.9 Hz,1H), 7.79 (s, 1H), 7.70 (d, J=2.2 Hz, 1H), 7.65-7.57 (m, 1H), 7.55-7.46(m, 1H), 6.38 (d, J=1.1 Hz, 1H), 4.60 (s, 2H).

149C. Preparation of(9R,13S)-13-(4-{5-chloro-2-[4-({3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy}methyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate

(9R,13S)-13-(4-{5-Chloro-2-[4-({3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy}methyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate (12.1 mg, 42.1% yield) was prepared in a similar manneras the procedure described in Example 56, by using6-{2-[4-(bromomethyl)-1H-1,2,3-triazol-1-yl]-5-chlorophenyl}pyrimidin-4-ol(12.3 mg, 0.033 mmol). MS(ESI) m/z: 704.24 (M+H)⁺. ¹H NMR (500 MHz,DMSO-d₆) δ 9.23 (s, 1H), 8.82-8.71 (m, 2H), 8.66-8.60 (m, 2H), 8.57 (d,J=8.2 Hz, 1H), 7.89 (d, J=2.4 Hz, 1H), 7.81 (dd, J=8.5, 2.1 Hz, 1H),7.65-7.59 (m, 2H), 7.56 (dd, J=8.4, 4.4 Hz, 1H), 7.51 (d, J=4.6 Hz, 1H),7.46 (s, 1H), 6.37 (s, 1H), 5.86 (d, J=11.3 Hz, 1H), 5.77 (s, 2H),4.03-3.91 (m, 3H), 3.55 (m., 1H), 2.62 (m, 1H), 2.23 (m, 1H), 2.05 (d,J=10.4 Hz, 1H), 1.86-1.73 (m, 1H), 1.41 (m, 1H), 1.29 (m, 1H), 0.85 (d,J=6.7 Hz, 3H), 0.39 (m., 1H). Analytical HPLC (Method C): RT=1.41 min,purity=95%; Factor XIa Ki=3.4 nM, Plasma Kallikrein Ki=310 nM.

Example 150 Preparation of(9R,13S)-13-(4-{5-chloro-2-[4-(hydroxylmethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate

150A. Preparation of6-{5-chloro-2-[4-(hydroxymethyl)-1H-1,2,3-triazol-1-yl]phenyl}pyrimidin-4-ol

A solution of{1-[4-chloro-2-(6-methoxypyrimidin-4-yl)phenyl]-1H-1,2,3-triazol-4-yl}methanol(65 mg, 0.205 mmol), prepared as described in Intermediate 16A, in 33%HBr in AcOH (0.6 ml, 4.97 mmol) was heated at 85° C. for 1 h. Thereaction was concentrated to half the volume, then 48% aq HBr (0.2 ml)was added and heated at 85° C. for 1 h. The reaction was concentrated,and the residue was partitioned between EtOAc and sat NaHCO₃. The layerswere separated and the aqueous layer was extracted with EtOAc (2×). Thecombined organic layers were concentrated and purified by normal phasechromatography to give6-{5-chloro-2-[4-(hydroxymethyl)-1H-1,2,3-triazol-1-yl]phenyl}pyrimidin-4-ol(13 mg, 20.9% yield). MS(ESI) m/z: 304.4 (M+H)⁺. ¹H NMR (400 MHz, CDCl₃)δ 7.99 (s, 1H), 7.76 (s, 2H), 7.59 (dd, J=8.5, 2.3 Hz, 1H), 7.49 (d,J=8.4 Hz, 1H), 6.18 (s, 1H), 4.83-4.76 (m, 2H).

150B. Preparation of(9R,13S)-13-(4-{5-chloro-2-[4-(hydroxymethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate

(9R,13S)-13-(4-{5-Chloro-2-[4-(hydroxymethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate (1.5 mg, 4.7% yield) was prepared in a similar manneras the procedure described in Example 56, by using6-(5-chloro-2-(4-(hydroxylmethyl)-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol(13.19 mg, 0.043 mmol). MS(ESI) m/z: 586.20 (M+H)⁺. ¹H NMR (500 MHz,DMSO-d₆) δ 9.26 (s, 1H), 8.82 (s, 1H), 8.68 (d, J=4.9 Hz, 1H), 8.23 (s,1H), 7.89 (d, J=1.8 Hz, 1H), 7.78 (d, J=6.4 Hz, 1H), 7.68-7.61 (m, 2H),7.56 (d, J=5.2 Hz, 1H), 7.47 (s, 1H), 6.15 (s, 1H), 5.90-5.82 (m, 1H),4.57 (d, J=4.9 Hz, 2H), 4.00 (s, 3H), 2.68-2.60 (m, 1H), 2.32-2.22 (m,1H), 2.07 (m, 1H), 1.88-1.78 (m, 1H), 1.50-1.43 (m, 1H), 1.40-1.29 (m,1H), 0.88 (d, J=6.7 Hz, 3H), 0.46-0.35 (m, 1H). Analytical HPLC (MethodC): RT=1.19 min, purity=92%; Factor XIa Ki=7.3 nM, Plasma KallikreinKi=1,400 nM.

Example 151 Preparation of(9R,13S)-13-(4-{5-chloro-2-[4-(difluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate

(9R,13S)-13-(4-{5-Chloro-2-[4-(difluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate (10 mg, 20.4% yield) was prepared in a similar manneras the procedure described in Example 56, by using6-{5-chloro-2-[4-(difluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}pyrimidin-4-ol(21.62 mg, 0.067 mmol), prepared as described in Intermediate 16.MS(ESI) m/z: 606.2 (M+H)⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.77 (s, 1H), 8.71(d, J=5.1 Hz, 1H), 8.53 (t, J=1.3 Hz, 1H), 7.88 (d, J=2.4 Hz, 1H),7.77-7.72 (m, 1H), 7.69 (s, 1H), 7.68-7.64 (m, 1H), 7.52 (dd, J=5.1, 1.5Hz, 1H), 7.49 (s, 1H), 7.14-6.84 (m, 1H), 6.35 (s, 1H), 5.97 (dd,J=12.5, 4.2 Hz, 1H), 4.04 (s, 3H), 2.70 (td, J=6.7, 3.1 Hz, 1H), 2.27(qd, J=8.5, 4.7 Hz, 1H), 2.12-1.92 (m, 2H), 1.65-1.53 (m, 1H), 1.45(ddd, J=14.6, 9.8, 5.3 Hz, 1H), 1.00 (d, J=6.8 Hz, 3H), 0.69 (m, 1H).¹⁹F NMR (376 MHz, CD₃OD) δ −77.76 (s), −114.46 (s). Analytical HPLC(Method A): RT=7.81 min, purity=98.7%; Factor XIa Ki=0.27 nM, PlasmaKallikrein Ki=54 nM.

Example 152 Preparation of(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate

152A. Preparation of4-{5-chloro-2-[4-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}-6-methoxypyrimidine

To a solution of 4-(trifluoromethyl)-1H-pyrazole (34.2 mg, 0.251 mmol)in DMF (698 μl) was added NaH (12.57 mg, 0.314 mmol) in 2 portions andthe reaction was stirred at rt for 30 min.4-(5-Chloro-2-fluorophenyl)-6-methoxypyrimidine (50 mg, 0.210 mmol),prepared as described in Intermediate 5A, was added and the solution wasstirred at rt for 2 h and then heated at 85° C. overnight. The reactionmixture was quenched with water and MeOH, then concentrated.Purification by normal phase chromatography gave4-{5-chloro-2-[4-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}-6-methoxypyrimidine(60 mg, 32.3% yield). MS(ESI) m/z: 355.3 (M+H)⁺. ¹H NMR (400 MHz, CDCl₃)δ 8.73 (d, J=0.9 Hz, 1H), 7.81 (s, 1H), 7.77 (d, J=2.4 Hz, 1H), 7.70 (s,1H), 7.59-7.53 (m, 1H), 7.51-7.47 (m, 1H), 6.36 (d, J=1.1 Hz, 1H),3.98-3.94 (m, 3H).

152B. Preparation of6-(5-chloro-2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)pyrimidin-4-ol

6-{5-Chloro-2-[4-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}pyrimidin-4-ol(23 mg, 25.5% yield) was prepared in a similar manner as the proceduredescribed in Intermediate 9E, by using4-{5-chloro-2-[4-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}-6-methoxypyrimidine(60 mg, 0.169 mmol). MS(ESI) m/z: 341.3 (M+H)⁺. ¹H NMR (400 MHz, CDCl₃)δ 7.97 (s, 1H), 7.90 (d, J=0.7 Hz, 1H), 7.82 (s, 1H), 7.70 (d, J=2.2 Hz,1H), 7.63-7.55 (m, 1H), 7.53-7.47 (m, 1H), 6.27 (d, J=0.9 Hz, 1H).

152C. Preparation of(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate

(9R,13S)-13-(4-{5-Chloro-2-[4-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate (20 mg, 40.2% yield) was prepared in a similar manneras the procedure described in Example 56, by using6-{5-chloro-2-[4-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}pyrimidin-4-ol(22.76 mg, 0.067 mmol). MS(ESI) m/z: 623.2 (M+H)⁺. ¹H NMR (400 MHz,CD₃OD) δ 8.85 (s, 1H), 8.71 (d, J=5.1 Hz, 1H), 8.32 (s, 1H), 7.90-7.80(m, 2H), 7.71-7.64 (m, 2H), 7.62-7.57 (m, 1H), 7.52 (dd, J=5.2, 1.7 Hz,1H), 7.49 (s, 1H), 6.20 (d, J=0.7 Hz, 1H), 5.98 (dd, J=12.7, 4.3 Hz,1H), 4.05 (s, 3H), 2.70 (td, J=6.7, 3.2 Hz, 1H), 2.30 (tt, J=12.7, 4.4Hz, 1H), 2.13-1.94 (m, 2H), 1.68-1.53 (m, 1H), 1.47 (ddd, J=14.9, 9.8,5.3 Hz, 1H), 1.01 (d, J=6.8 Hz, 3H), 0.70 (m, 1H). ¹⁹F NMR (376 MHz,CD₃OD) δ −57.99 (s), −77.75 (s). Analytical HPLC (Method A): RT=8.98min, purity=99.1%; Factor XIa Ki=10 nM, Plasma Kallikrein Ki=4,900 nM.

Example 153 Preparation of(9R,13S)-13-(4-{5-chloro-2-[4-(fluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate

153A. Preparation of6-{5-chloro-2-[4-(fluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}pyrimidin-4-ol

A solution of4-{5-chloro-2-[4-(fluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-methoxypyrimidine(35 mg, 0.109 mmol), prepared as described in Example 149A in ACN (1 mL)was treated with TMSI (75 μL, 0.55 mmol) and heated at 50° C. for 6 h.The reaction was poured into 10% aq Na₂S₂O₃. Sat NaHCO₃ was added andthe mixture was extracted with EtOAc (2×). The combined organic layerswere washed with brine, concentrated, and purified by normal phasechromatography to give6-{5-chloro-2-[4-(fluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}pyrimidin-4-ol(14 mg, 41.8% yield). MS(ESI) m/z: 306.4 (M+H)⁺. ¹H NMR (400 MHz, CDCl₃)δ 7.98 (s, 1H), 7.84 (d, J=2.4 Hz, 1H), 7.74 (d, J=2.4 Hz, 1H), 7.62(dd, J=8.5, 2.3 Hz, 1H), 7.49 (d, J=8.4 Hz, 1H), 6.36 (s, 1H), 5.55 (d,J=48.2 Hz, 1H). ¹⁹F NMR (376 MHz, CDCl₃) δ −208.21 (s).

153B. Preparation of(9R,13S)-13-(4-{5-chloro-2-[4-(fluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate

(9R,13S)-13-(4-{5-Chloro-2-[4-(fluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate (12 mg, 37% yield) was prepared in a similar manner asthe procedure described in Example 56, by replacing6-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}pyrimidin-4-olwith6-{5-chloro-2-[4-(fluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}pyrimidin-4-ol(14 mg, 0.046 mmol). MS(ESI) m/z: 588.3 (M+H)⁺. ¹H NMR (400 MHz, CD₃OD)δ 8.79 (s, 1H), 8.71 (d, J=5.1 Hz, 1H), 8.35 (d, J=3.1 Hz, 1H), 7.88 (d,J=2.4 Hz, 1H), 7.75-7.70 (m, 1H), 7.68 (s, 1H), 7.66-7.62 (m, 1H), 7.52(dd, J=5.3, 1.5 Hz, 1H), 7.48 (s, 1H), 6.29 (s, 1H), 5.96 (dd, J=12.5,4.2 Hz, 1H), 5.47 (d, J=48.6 Hz, 2H), 4.04 (s, 3H), 2.70 (td, J=6.7, 3.3Hz, 1H), 2.33-2.20 (m, 1H), 2.12-1.92 (m, 2H), 1.66-1.53 (m, 1H),1.52-1.37 (m, 1H), 1.00 (d, J=7.0 Hz, 3H), 0.69 (m, 1H). ¹⁹F NMR (376MHz, CD₃OD) δ −77.74 (s), −207.90 (s). Analytical HPLC (Method A):RT=7.01 min, purity=98.5%; Factor XIa Ki=1.4 nM, Plasma KallikreinKi=150 nM.

Example 154 Preparation of1-(4-chloro-2-{1-[(9R,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)-1H-1,2,3-triazole-4-carbonitriletrifluoroacetate

1-(4-Chloro-2-{1-[(9R,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)-1H-1,2,3-triazole-4-carbonitriletrifluoroacetate (8 mg, 18% yield) was prepared in a similar manner asthe procedure described in Example 56, by using1-[4-chloro-2-(6-hydroxypyrimidin-4-yl)phenyl]-1H-1,2,3-triazole-4-carbonitrile(17.81 mg, 0.060 mmol), prepared as described in Intermediate 18.MS(ESI) m/z: 617.2 (M+H). ¹H NMR (400 MHz, CD₃OD) δ 8.93 (s, 1H), 8.79(s, 1H), 8.75 (d, J=5.1 Hz, 1H), 7.89 (d, J=2.2 Hz, 1H), 7.81-7.63 (m,5H), 7.54-7.48 (m, 1H), 6.47 (d, J=0.7 Hz, 1H), 5.99 (dd, J=12.8, 4.4Hz, 1H), 2.76-2.65 (m, 1H), 2.34-2.22 (m, 1H), 2.09-1.94 (m, 2H),1.65-1.40 (m, 2H), 0.99 (d, J=6.8 Hz, 3H), 0.71-0.54 (m, 1H). AnalyticalHPLC (Method A): RT=9.04 min, purity=99.0%; Factor XIa Ki=0.1 nM, PlasmaKallikrein Ki=17 nM.

Example 155 Preparation of(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(²H₃)methyl-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate

(9R,13S)-13-(4-{5-Chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(²H₃)methyl-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate (11 mg, 30% yield) was prepared in a similar manner asthe procedure described in Example 56, by using(9R,13S)-13-amino-3-(²H₃)methyl-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(15 mg, 0.050 mmol), prepared as described in Intermediate 33. MS(ESI)m/z: 627.3 (M+H). ¹H NMR (400 MHz, CD₃OD) δ 8.81 (s, 1H), 8.77-8.66 (m,2H), 7.89 (d, J=2.2 Hz, 1H), 7.79-7.64 (m, 3H), 7.59-7.51 (m, 1H), 7.49(s, 1H), 6.44 (s, 1H), 5.97 (dd, J=12.4, 3.9 Hz, 1H), 2.76-2.62 (m,J=6.5, 3.4, 3.4 Hz, 1H), 2.34-2.21 (m, 1H), 2.12-1.94 (m, 2H), 1.68-1.53(m, 1H), 1.51-1.39 (m, 1H), 1.00 (d, J=6.8 Hz, 3H), 0.78-0.63 (m, 1H).Analytical HPLC (Method A): RT=8.64 min, purity=99.4%; Factor XIaKi=0.14 nM, Plasma Kallikrein Ki=33 nM.

Example 156 Preparation of(9R,13S)-13-(4-{5-chloro-2-[4-(difluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate

(9R,13S)-13-(4-{5-Chloro-2-[4-(difluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate (22 mg, 57% yield) was prepared in a similar manner asthe procedure described in Example 56, using6-{5-chloro-2-[4-(difluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}pyrimidin-4-ol(16.41 mg, 0.051 mmol), prepared as described in Intermediate 16, and(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(17 mg, 0.051 mmol), prepared as described in Intermediate 30. MS(ESI)m/z: 642.3 (M+H). ¹H NMR (400 MHz, CD₃OD) δ 8.84 (s, 1H), 8.72 (d, J=5.1Hz, 1H), 8.53 (t, J=1.4 Hz, 1H), 7.89 (d, J=2.2 Hz, 1H), 7.81-7.62 (m,5H), 7.54-7.48 (m, 1H), 6.99 (t, J=54.4 Hz, 1H), 6.35 (d, J=0.7 Hz, 1H),6.00 (dd, J=12.9, 4.7 Hz, 1H), 2.70 (td, J=6.7, 3.0 Hz, 1H), 2.33-2.19(m, 1H), 2.08-1.93 (m, 2H), 1.64-1.51 (m, 1H), 1.51-1.39 (m, 1H), 0.99(d, J=7.0 Hz, 3H), 0.68-0.52 (m, 1H). Analytical HPLC (Method A):RT=10.94 min, purity=99.0%; Factor XIa Ki=0.22 nM, Plasma KallikreinKi=50 nM.

Example 157 Preparation of(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate

(9R,13S)-13-(4-{5-Chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate (20 mg, 50% yield) was prepared in a similar manner asthe procedure described in Example 56, by using(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(17 mg, 0.051 mmol), prepared as described in Intermediate 30. MS(ESI)m/z: 660.3 (M+H). ¹H NMR (400 MHz, CD₃OD) δ 8.81 (d, J=3.7 Hz, 2H), 8.71(d, J=5.1 Hz, 1H), 7.89 (d, J=2.2 Hz, 1H), 7.81-7.62 (m, 5H), 7.56-7.46(m, 1H), 6.44 (s, 1H), 6.00 (dd, J=12.7, 4.5 Hz, 1H), 2.70 (td, J=6.5,3.0 Hz, 1H), 2.32-2.20 (m, 1H), 2.10-1.91 (m, 2H), 1.65-1.51 (m, 1H),1.51-1.39 (m, 1H), 0.99 (d, J=6.8 Hz, 3H), 0.70-0.51 (m, 1H). AnalyticalHPLC (Method A): RT=9.74 min, purity=97.8%; Factor XIa Ki=0.1 nM, PlasmaKallikrein Ki=34 nM.

Example 158 Preparation of(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(²H₃)methyl-9-methyl-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate

(9R,13S)-13-(4-{5-Chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(²H₃)methyl-9-methyl-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate (12 mg, 36% yield) was prepared in a similar manner asthe procedure described in Example 56, by using(9R,13S)-13-amino-3-(²H₃)methyl-9-methyl-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(16 mg, 0.053 mmol), prepared as described in Intermediate 36. MS(ESI)m/z: 626.3 (M+H)⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.76 (d, J=0.7 Hz, 1H),8.10 (s, 1H), 7.86 (d, J=2.2 Hz, 1H), 7.76-7.71 (m, 2H), 7.69-7.63 (m,1H), 7.60-7.50 (m, 2H), 7.49 (s, 1H), 7.31-7.24 (m, 1H), 6.47 (d, J=0.4Hz, 1H), 5.81 (dd, J=12.8, 3.3 Hz, 1H), 2.46 (ddd, J=10.3, 6.8, 3.6 Hz,1H), 2.38-2.23 (m, 1H), 2.13-1.98 (m, 1H), 1.91-1.78 (m, 1H), 1.63-1.47(m, 2H), 1.27-1.15 (m, 1H), 1.13 (d, J=6.8 Hz, 3H). Analytical HPLC(Method A): RT=9.06 min, purity=99.2%; Factor XIa Ki=0.1 nM, PlasmaKallikrein Ki=8 nM.

Example 159 Preparation of(9S,13R)-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

159A. Preparation of(R)—N-((4-chloropyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide

To a RBF was added 4-chloropicolinaldehyde (5.0 g, 35.3 mmol), CH₂Cl₂(100 mL), (R)-2-methylpropane-2-sulfinamide (5.14 g, 42.4 mmol) andCs₂CO₃ (34.5 g, 106 mmol). The reaction was stirred at rt overnight. Thereaction was filtered through CELITE®. The filtrate was concentrated andthe residue was purified using ISCO system (0-50% EtOAc/Hep gradient) togive(R)—N-((4-chloropyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide(6.36 g, 26.0 mmol, 73.6% yield) as a clear oil. ¹H NMR (400 MHz, CDCl₃)δ 8.71 (s, 1H), 8.67 (dd, J=5.3, 0.4 Hz, 1H), 8.05 (dd, J=2.0, 0.4 Hz,1H), 7.44 (dd, J=5.3, 2.0 Hz, 1H), 1.33 (s, 9H); MS(ESI) m/z: 245.1(M+H)⁺.

159B. Preparation of(R)—N—((R)-1-(4-chloropyridin-2-yl)but-3-en-1-yl)-2-methylpropane-2-sulfinamide

To a RBF was added(R)—N-((4-chloropyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide(6.39 g, 26.1 mmol), THF (40 mL), 3-bromoprop-1-ene (3.39 mL, 39.2 mmol)and In (4.50 g, 39.2 mmol). The reaction was stirred at 60° C.overnight. The reaction was then partitioned between EtOAc (100 ml) andwater (50 ml). The organic layer was separated, washed with sat NaCl (50ml), dried over MgSO₄, filtered and concentrated. The residue waspurified using ISCO system (0-100% EtOAc/Hep gradient) to give(R)—N—((R)-1-(4-chloropyridin-2-yl)but-3-en-1-yl)-2-methylpropane-2-sulfinamide(5.67 g, 19.8 mmol, 76% yield) as a clear oil. ¹H NMR (500 MHz, CDCl₃) δ8.50-8.41 (m, 1H), 7.36-7.30 (m, 1H), 7.26-7.18 (m, 1H), 5.71 (ddt,J=17.1, 10.3, 6.9 Hz, 1H), 5.12-4.99 (m, 2H), 4.77 (d, J=7.4 Hz, 1H),4.48 (q, J=6.8 Hz, 1H), 2.66-2.51 (m, 2H), 1.30-1.27 (m, 9H); MS(ESI)m/z: 287.1 (M+H)⁺.

159C. Preparation of (R)-tert-butyl(1-(4-chloropyridin-2-yl)but-3-en-1-yl)carbamate

To a RBF was added(R)—N—((R)-1-(4-chloropyridin-2-yl)but-3-en-1-yl)-2-methylpropane-2-sulfinamide(5.67 g, 19.77 mmol), MeOH (100 mL) and 4 N HCl in dioxane (24.71 mL, 99mmol). The reaction was stirred at rt for 30 min. The reaction was thenconcentrated to give a white solid. To this solid was added CH₂Cl₂ (100mL), Et₃N (5.51 mL, 39.5 mmol) and (Boc)₂O (5.51 mL, 23.72 mmol). Thereaction was stirred at rt overnight. The reaction was diluted withCH₂Cl₂ (100 ml) and washed with water (100 ml) and sat NaCl (100 ml),dried over MgSO₄, filtered and concentrated. The residue was purifiedusing ISCO system (0-50% EtOAc/Hex gradient) to give (R)-tert-butyl(1-(4-chloropyridin-2-yl)but-3-en-1-yl)carbamate (4.92 g, 17.40 mmol,88% yield) as a clear oil. ¹H NMR (500 MHz, CDCl₃) δ 8.47 (d, J=5.2 Hz,1H), 7.27 (d, J=1.7 Hz, 1H), 7.21 (dd, J=5.2, 1.9 Hz, 1H), 5.80-5.60 (m,1H), 5.49 (d, J=5.8 Hz, 1H), 5.15-5.00 (m, 2H), 4.81 (d, J=6.1 Hz, 1H),2.67-2.50 (m, 2H), 1.50-1.39 (m, 9H); MS(ESI) m/z: 283.1 (M+H)⁺.

159D. Preparation of (R)-tert-butyl(1-(4-(1-(difluoromethyl)-4-nitro-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate

To a RBF was added (R)-tert-butyl(1-(4-chloropyridin-2-yl)but-3-en-1-yl) carbamate (2.54 g, 15.56 mmol),di(adamantan-1-yl)(butyl)phosphine (0.507 g, 1.415 mmol), K₂CO₃ (5.87 g,42.4 mmol), pivalic acid (0.433 g, 4.24 mmol) and dioxane (50 mL). Thereaction mixture was purged with Ar for 5 min. To this mixture was addedPd(OAc)₂ (0.159 g, 0.707 mmol) and the reaction was heated at 100° C.for 4 h. The reaction was then partitioned with water (200 mL) and EtOAc(200 mL). The organic layer was separated and washed with water (200 mL)and sat NaCl (200 mL), dried over MgSO₄, filtered and concentrated togive the crude product which was then purified using ISCO system (0-60%EtOAc/Hex gradient) to give (R)-tert-butyl(1-(4-(1-(difluoromethyl)-4-nitro-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate(4.12 g, 10.06 mmol, 71.1% yield) as a yellow oil. ¹H NMR (500 MHz,CDCl₃) δ 8.82-8.78 (m, 1H), 8.36 (s, 1H), 7.34 (s, 1H), 7.32-7.30 (m,1H), 7.23-6.96 (m, 1H), 5.76-5.65 (m, 1H), 5.59 (d, J=5.8 Hz, 1H),5.14-5.04 (m, 2H), 4.93 (d, J=5.8 Hz, 1H), 2.67 (t, J=6.1 Hz, 2H), 1.46(br. s., 9H); MS(ESI) m/z: 410.1 (M+H)⁺.

159E. Preparation of (R)-tert-butyl(1-(4-(4-amino-1-(difluoromethyl)-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate

To a round bottom was added (R)-tert-butyl(1-(4-(1-(difluoromethyl)-4-nitro-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate(4.12 g, 10.06 mmol), Zn (2.63 g, 40.3 mmol) MeOH (40 mL) and AcOH (4mL). The reaction was heated in at 40° C. for 10 min. The reaction wasthen cooled to rt and partitioned between EtOAc (100 ml) and sat NaHCO₃(100 ml). The organic layer was separated, washed with water (100 ml)and sat NaCl (100 ml), dried over MgSO₄, filtered and concentrated. Theresidue was purified using ISCO system (0-30% MeOH/CH₂Cl₂ gradient) togive (R)-tert-butyl(1-(4-(4-amino-1-(difluoromethyl)-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate(3.37 g, 8.88 mmol, 88% yield) as a yellow oil. ¹H NMR (500 MHz, CDCl₃)δ 8.73-8.68 (m, 1H), 7.43 (s, 1H), 7.36 (s, 1H), 7.33 (d, J=5.0 Hz, 1H),7.26-7.00 (m, 1H), 5.80-5.67 (m, 1H), 5.59 (br. s., 1H), 5.10 (s, 1H),5.07 (d, J=4.4 Hz, 1H), 4.88 (d, J=6.1 Hz, 1H), 2.66 (t, J=6.2 Hz, 2H),1.50-1.40 (m, 9H); MS(ESI) m/z: 380.1 (M+H)⁺.

159F. Preparation of tert-butyl((1R)-1-(4-(1-(difluoromethyl)-4-(2-methylbut-3-enamido)-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate

To a RBF was added (R)-tert-butyl(1-(4-(4-amino-1-(difluoromethyl)-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate(3.37 g, 8.88 mmol), EtOAc (20 mL), 2-methylbut-3-enoic acid (0.889 g,8.88 mmol) and pyridine (1.44 mL, 17.76 mmol). The solution was cooledin an ice bath and2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (7.93mL, 13.32 mmol) was added. The reaction was stirred at 0° C. for 2 h.The reaction was then partitioned between EtOAc (100 ml) and sat NaHCO₃(100 ml). The organic layer was separated, washed with water (100 ml)and brine (100 ml), dried over MgSO₄, filtered and concentrated. Theresidue was purified using ISCO system (0-80% EtOAc/Hex gradient) togive tert-butyl((1R)-1-(4-(1-(difluoromethyl)-4-(2-methylbut-3-enamido)-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate(3.33 g, 7.22 mmol, 81% yield) as a yellow oil. It was a mixture of 2diastereomers. ¹H NMR (500 MHz, CDCl₃) δ 8.74 (d, J=5.0 Hz, 1H), 8.36(d, J=2.2 Hz, 1H), 7.34-7.30 (m, 1H), 7.28-7.24 (m, 1H), 7.22-7.06 (m,2H), 5.98-5.83 (m, 1H), 5.76-5.65 (m, 1H), 5.51 (br. s., 1H), 5.28-5.18(m, 2H), 5.15-5.03 (m, 2H), 4.86 (br. s., 1H), 3.22-3.04 (m, 1H), 2.66(br. s., 2H), 1.50-1.42 (m, 9H), 1.33 (dd, J=7.0, 4.5 Hz, 3H); MS(ESI)m/z: 462.2 (M+H)⁺.

159G and 159H. Preparation of tert-butylN-[(9S,13R)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate,and tert-butylN-[(9R,13R)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate

To a RBF was added tert-butyl((1R)-1-(4-(1-(difluoromethyl)-4-(2-methylbut-3-enamido)-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate(3.33 g, 7.22 mmol) and EtOAc. Second Generation Grubbs Catalyst (1.531g, 1.804 mmol) was added to the reaction. The reaction was refluxedunder Ar for 2 days. The reaction was concentrated. The residue waspurified using ISCO system (0-100% EtOAc/Hex gradient and then 100%EtOAc). Two diastereomers were separated. The compound that came off thecolumn first was 159G, tert-butylN-[(9S,13R)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate(490 mg, 1.13 mmol, 15.7% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.72 (d,J=5.1 Hz, 1H), 7.80 (s, 1H), 7.42 (s, 1H), 7.27 (m, 1H), 7.20 (br. s.,1H), 6.87 (s, 1H), 6.41 (d, J=7.5 Hz, 1H), 5.77 (ddd, J=15.2, 11.0, 4.0Hz, 1H), 4.89-4.70 (m, 2H), 3.19-3.08 (m, 1H), 3.03 (d, J=12.5 Hz, 1H),2.03-1.92 (m, 1H), 1.50 (s, 9H), 1.20 (d, J=6.6 Hz, 3H); MS(ESI) m/z:434.1 (M+H)⁺. The compound that came off the column second was 159H,tert-butylN-[(9R,13R)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate(460 mg, 1.06 mmol, 14.7% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.71 (d,J=5.1 Hz, 1H), 7.83 (s, 1H), 7.37 (d, J=5.1 Hz, 1H), 7.26 (d, J=2.6 Hz,1H), 6.89 (s, 1H), 6.68 (br. s., 1H), 6.28 (br. s., 1H), 5.84-5.69 (m,1H), 5.47-5.32 (m, 1H), 4.82 (br. s., 1H), 3.11-2.90 (m, 2H), 2.15-1.98(m, 1H), 1.52-1.44 (m, 9H), 1.37 (d, J=6.6 Hz, 3H); MS(ESI) m/z: 434.1(M+H)⁺.

159I. Preparation of tert-butylN-[(9S,13R)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate

To a 3-neck RBF wad added tert-butylN-[(9S,13R)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate(485 mg, 1.119 mmol), EtOH (35 mL) and PtO₂ (127 mg, 0.559 mmol). Thereaction was stirred under a H₂ balloon for 1 h. The reaction wascarefully filtered through CELITE® and the filtrate was concentrated.The residue was purified using ISCO system (0-10% MeOH/CH₂Cl₂ gradient)to give tert-butylN-[(9S,13R)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate(370 mg, 0.850 mmol, 76% yield) as a beige solid. ¹H NMR (400 MHz,CDCl₃) δ 8.75 (d, J=5.1 Hz, 1H), 7.63 (s, 1H), 7.46 (s, 1H), 7.35 (s,1H), 7.31 (m, J=3.5 Hz, 1H), 6.81 (br. s., 1H), 5.81 (d, J=7.9 Hz, 1H),4.88 (br. s., 1H), 2.62 (td, J=6.5, 2.6 Hz, 1H), 2.13-1.99 (m, 1H),1.90-1.77 (m, 1H), 1.69-1.62 (m, 1H), 1.56-1.51 (m, 1H), 1.49-1.41 (m,9H), 1.31-1.17 (m, 1H), 1.03 (d, J=6.8 Hz, 3H), 0.41 (d, J=12.1 Hz, 1H);MS(ESI) m/z: 436.1 (M+H)⁺.

159J. Preparation of(9S,13R)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

To a RBF was added tert-butylN-[(9S,13R)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate(370 mg, 0.850 mmol), dioxane (1 mL), MeOH (1 mL) and 4 N HCl (6.37 mL,25.5 mmol). The reaction was stirred at rt for 1 h. The reaction wasconcentrated to give the product as HCl salt. This HCl salt wasdissolved in MeOH and was added to a pre-rinsed AGILENT® StratoSpheresSPE PL-HCO₃ MP Resin cartridge. Gravity filtration, eluting with MeOH,gave a clear, slightly brown filtrate. Concentration provided(9S,13R)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(285 mg, 0.850 mmol, 100% yield) as a light brown solid. MS(ESI) m/z:336.1 (M+H)⁺.

159K. Preparation of(9S,13R)-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

(9S,13R)-{4-[5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(230 mg, 360 μmol, 42.3% yield) was prepared in a similar manner as theprocedure described in Example 56 by using6-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol (331mg, 0.850 mmol), prepared as described in Intermediate 9, and(9S,13R)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(285 mg, 0.850 mmol). ¹H NMR (400 MHz, CD₃OD) δ 8.90 (s, 1H), 8.76 (d,J=5.1 Hz, 1H), 8.35 (s, 1H), 7.90 (d, J=2.4 Hz, 1H), 7.78-7.73 (m, 2H),7.71 (d, J=0.7 Hz, 1H), 7.68 (t, 1H), 7.65 (s, 1H), 7.55-7.53 (m, 1H),6.39 (d, J=0.9 Hz, 1H), 6.03 (dd, J=12.8, 4.4 Hz, 1H), 2.73 (td, J=6.5,3.0 Hz, 1H), 2.31 (tt, J=12.8, 4.3 Hz, 1H), 2.11-1.97 (m, 2H), 1.67-1.44(m, 2H), 1.01 (d, J=7.0 Hz, 3H), 0.64 (br. s., 1H); MS(ESI) m/z: 626.1(M+H)⁺. Analytical HPLC (Method A): RT=7.96 min, purity=95.0%; FactorXIa Ki=14 nM, Plasma Kallikrein Ki=880 nM.

Example 160 Preparation of(9R,13R)-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

160A. Preparation of tert-butylN-[(9R,13R)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate

To a 3-neck RBF wad added tert-butylN-[(9R,13R)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate(450 mg, 1.038 mmol), EtOH (35 mL) and PtO₂ (118 mg, 0.519 mmol). Thereaction was stirred under a H₂ balloon for 1 h. The reaction wascarefully filtered through CELITE® and the filtrate was concentrated.The residue was purified using ISCO system (0-10% MeOH/CH₂Cl₂ gradient)to give tert-butylN-[(9R,13R)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate(300 mg, 0.689 mmol, 66.4% yield) as a beige solid. ¹H NMR (400 MHz,CDCl₃) δ 8.73 (d, J=5.3 Hz, 1H), 7.69 (s, 1H), 7.40 (d, J=5.1 Hz, 1H),7.30 (m, J=4.2 Hz, 1H), 6.49 (br. s., 1H), 5.90 (d, J=7.0 Hz, 1H), 4.88(br. s., 1H), 2.25-2.14 (m, 1H), 2.07 (d, J=9.5 Hz, 1H), 1.91-1.77 (m,1H), 1.47 (s, 11H), 1.27 (d, J=6.8 Hz, 3H), 0.74 (d, J=11.2 Hz, 1H);MS(ESI) m/z: 436.1 (M+H)⁺.

160B. Preparation of(9R,13R)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

To a RBF was added tert-butylN-[(9R,13R)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate(300 mg, 0.689 mmol), dioxane (1 mL), MeOH (1 mL) and 4 N HCl (6.37 mL,25.5 mmol). The reaction was stirred at rt for 1 h. The reaction wasconcentrated to give the product as HCl salt. This HCl salt wasdissolved in MeOH and was added to a pre-rinsed AGILENT® StratoSpheresSPE PL-HCO₃ MP Resin cartridge. Gravity filtration, eluting with MeOH,gave a clear, slightly brown filtrate. Concentration provided(9R,13R)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(220 mg, 0.656 mmol, 95% yield) as a light brown solid. MS(ESI) m/z:336.1 (M+H)⁺.

160C. Preparation of(9R,13R)-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

(9R,13R)-{4-[5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(140 mg, 219 μmol, 33.4% yield) was prepared in a similar manner as theprocedure described in Example 56 by using6-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol (255mg, 0.656 mmol), prepared as described in Intermediate 9, and(9R,13R)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(225 mg, 0.656 mmol). ¹H NMR (400 MHz, CD₃OD) δ 8.83 (s, 1H), 8.74 (d,J=5.1 Hz, 1H), 8.36 (s, 1H), 7.91 (d, J=2.2 Hz, 1H), 7.79 (s, 1H),7.78-7.74 (m, 1H), 7.69 (t, 1H), 7.68-7.66 (m, 1H), 7.60 (s, 1H), 7.51(d, J=4.8 Hz, 1H), 6.42 (d, J=0.7 Hz, 1H), 6.07 (dd, J=12.7, 4.3 Hz,1H), 2.38-2.28 (m, 1H), 2.25-2.15 (m, 1H), 2.05-1.90 (m, 2H), 1.64-1.50(m, 2H), 1.27 (d, J=6.8 Hz, 3H), 0.83 (d, J=13.6 Hz, 1H); MS(ESI) m/z:626.1 (M+H)⁺. Analytical HPLC (Method A): RT=10.37 min, purity=97.0%;Factor XIa Ki=18 nM, Plasma Kallikrein Ki=3,200 nM.

Example 161 Preparation of(9R,13S)-13-{4-[5-chloro-2-(pyridin-3-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

In a microwave vial was added(9R,13S)-13-[4-(2-bromo-5-chlorophenyl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(0.02 g, 0.035 mmol), prepared in Example 138, pyridin-3-ylboronic acid(4.76 mg, 0.039 mmol), 3 M aq K₃PO₄ (0.035 ml, 0.106 mmol) and THF (1ml). Ar was bubbled through the reaction for several min and then(DtBPF)PdCl₂ (1.15 mg, 1.761 μmol) was added. The reaction mixture wasmicrowaved at 150° C. for 1 h, cooled to rt, and concentrated.Purification by reverse phase chromatography afforded(9R,13S)-13-{4-[5-chloro-2-(pyridin-3-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate (3.21 mg, 12% yield) as a yellow solid. MS(ESI) m/z:566.2 (M+H)⁺. ¹H NMR (500 MHz, CD₃OD) δ 8.79-8.68 (m, 4H), 8.34 (dt,J=8.2, 1.7 Hz, 1H), 7.90 (dd, J=8.0, 5.8 Hz, 1H), 7.81 (d, J=2.2 Hz,1H), 7.71-7.66 (m, 2H), 7.57 (d, J=8.3 Hz, 1H), 7.53-7.47 (m, 2H), 6.52(d, J=0.5 Hz, 1H), 5.98-5.90 (m, 1H), 4.04 (s, 3H), 2.74-2.64 (m, 1H),2.30-2.19 (m, 1H), 2.10-1.93 (m, 2H), 1.63-1.53 (m, 1H), 1.50-1.40 (m,1H), 1.00 (d, J=6.9 Hz, 3H), 0.77-0.61 (m, 1H). Analytical HPLC (MethodA): RT=4.22 min, 99.8% purity; Factor XIa Ki=100 nM, Plasma KallikreinKi=5,700 nM.

Example 162 Preparation of(9R,13S)-13-(4-{5-chloro-2-[4-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

162A. Preparation of6-{5-chloro-2-[4-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl]phenyl}pyrimidin-4-ol

6-{5-Chloro-2-[4-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl]phenyl}pyrimidin-4-olwas prepared by the condensation of an ACN (5 ml) solution consisting of6-(2-azido-5-chlorophenyl)pyrimidin-4-ol (0.9 g, 3.44 mmol) and2-methylbut-3-yn-2-ol (0.289 g, 3.44 mmol) in the presence Cu₂O (0.05g). The product, after ISCO silica gel chromatography with hexane:EtOAcas eluants, was obtained as an oil (0.5 g). ¹H NMR (400 MHz, CDCl₃) δ8.60-8.57 (m, 1H), 7.65-7.59 (m, 1H), 7.56-7.53 (m, 1H), 7.37-7.32 (m,1H), 6.76-6.72 (m, 1H), 3.95 (s, 3H), 3.43-3.30 (m, 1H), 1.52 (s, 6H).The oil was then dissolved in AcOH (1 ml) and to this was added 48% aqHBr (0.5 ml) and the reaction was sealed. The reaction mixture washeated at 80° C. for 2 h and then concentrated to a gummy solid andwater (10 ml) was added. A solid precipitated and was collected bydecanting the solution. The solid was washed several times with waterand the residue was dissolved in MeOH and the solution was concentratedto give6-{5-chloro-2-[4-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl]phenyl}pyrimidin-4-ol(0.15 g, 13%) as a foam. LCMS m/z=332.1 (M+H)⁺. ¹H NMR (400 MHz, CDCl₃)δ 11.51-11.06 (m, 1H), 8.33-8.09 (m, 1H), 7.90-7.78 (m, 1H), 7.71 (t,J=7.9 Hz, 1H), 7.39-7.29 (m, 1H), 6.87-6.68 (m, 1H), 5.80-5.66 (m, 1H),5.27-5.17 (m, 1H), 2.12 (s, 6H).

162B. Preparation of(9R,13S)-13-(4-{5-chloro-2-[4-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

(9R,13S)-13-(4-{5-Chloro-2-[4-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onewas prepared (4.2 mg, 21% yield) as a solid via the coupling of6-{5-chloro-2-[4-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl]phenyl}pyrimidin-4-ol(0.01 g, 0.030 mmol) and(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(0.010 g, 0.030 mmol) using the HATU, DBU coupling methodology asdescribed in Example 56. MS m/z=651.1 (M+H)⁺. ¹H NMR (500 MHz, DMSO-d₆)δ 9.46-9.40 (m, 1H), 8.88-8.82 (m, 1H), 8.72-8.65 (m, 1H), 8.40-8.36 (m,1H), 8.01-7.93 (m, 2H), 7.89 (s, 1H), 7.72-7.68 (m, 1H), 7.68-7.61 (m,1H), 7.46-7.40 (m, 1H), 6.63-6.57 (m, 1H), 5.94-5.85 (m, 1H), 5.70-5.64(m, 1H), 5.15-5.08 (m, 1H), 2.71-2.61 (m, 1H), 2.56 (s, 3H), 2.35-2.16(m, 1H), 2.08-2.04 (m, 4H), 2.07-1.79 (m, 1H), 1.56-1.26 (m, 1H),0.93-0.79 (d, 3H), 0.44-0.24 (m, 1H). Analytical HPLC (Method B):RT=1.75 min, purity=97%; Factor XIa Ki=1 nM, Plasma Kallikrein Ki=230nM.

Example 163 Preparation of(9R,13S)-3-(difluoromethyl)-9-methyl-13-(6-oxo-4-{2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl)}-1,6-dihydropyrimidin-1-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

(9R,13S)-3-(Difluoromethyl)-9-methyl-13-(6-oxo-4-{2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-1,6-dihydropyrimidin-1-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onewas prepared (1.6 mg, 6.2% yield) as a solid via the coupling of6-{2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}pyrimidin-4-ol(0.012 g, 0.04 mmol) and(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one (0.013 g, 0.04 mmol) using the HATU, DBU couplingmethodology as described in Example 56. LCMS m/z=626.2 (M+H)⁺. ¹H NMR(500 MHz, DMSO-d₆) δ 9.46-9.42 (m, 1H), 9.20-9.15 (m, 1H), 8.76-8.67 (m,2H), 7.89-7.83 (m, 2H), 7.80-7.73 (m, 3H), 7.70-7.64 (m, 1H), 7.46-7.39(m, 1H), 6.42-6.36 (m, 1H), 5.94-5.86 (m, 1H), 2.70-2.60 (m, 1H),2.31-2.18 (m, 1H), 2.10-1.94 (m, 1H), 1.88-1.77 (m, 1H), 1.52-1.28 (m,2H), 0.91-0.82 (d, 3H), 0.49-0.19 (m, 1H). Analytical HPLC (Method B)RT=1.65 min, purity=96%; Factor XIa Ki=10 nM, Plasma Kallikrein Ki=5,900nM.

Example 164 Preparation of(9R,13S)-3-(difluoromethyl)-13-(4-{5-fluoro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

(9R,13S)-3-(Difluoromethyl)-13-(4-{5-fluoro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onewas prepared (8 mg, 26% yield) as a solid via the coupling of6-{5-fluoro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}pyrimidin-4-ol(0.015 g, 0.05 mmol) and(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one (0.015 g, 0.05 mmol) using the HATU, DBU couplingmethodology described in Example 56. LCMS m/z=644.2 (M+H). ¹H NMR (400MHz, CD₃OD) δ 8.80-8.72 (m, 3H), 7.82-7.78 (m, 1H), 7.75-7.70 (m, 2H),7.66-7.60 (m, 2H), 7.52-7.43 (m, 1H), 6.44-6.41 (m, 1H), 6.01-5.95 (m,1H), 2.75-2.66 (m, 1H), 2.38-2.25 (m, 1H), 2.08-1.92 (m, 2H), 1.64-1.39(m, 2H), 1.07-0.95 (d, 3H), 0.79-0.54 (m, 1H). Analytical HPLC (MethodA) RT=8.22 min, purity=99%; Factor XIa Ki=5 nM, Plasma KallikreinKi=1,100 nM.

Example 165 Preparation of(9R,13S)-13-{4-[5-chloro-2-(4-hydroxy-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-ihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate

165A. Preparation of6-(5-chloro-2-(4-hydroxy-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol

To a solution of6-(5-chloro-2-(4-ethoxy-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol,hydrobromide (0.027 g, 0.068 mmol) in DCM (1 ml) was added AlCl₃ (0.090g, 0.68 mmol). The reaction was microwaved at 100° C. for 10 min, cooledto rt. Next the reaction was cooled in a dry ice/acetone bath and MeOH(1 ml) was added slowly. The reaction was allowed to warm to rt and thereaction was stirred until a solution formed. 1 N HCl (1 ml) was addedand the resulting mixture was concentrated to dryness. Purification byreverse phase chromatography afforded6-(5-chloro-2-(4-hydroxy-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol(0.012 g, 61.2% yield) as a white solid. MS(ESI) m/z: 290.3 (M+H)⁺. ¹HNMR (400 MHz, CD₃OD) δ 8.11 (s, 1H), 7.82 (d, J=2.4 Hz, 1H), 7.72-7.67(m, 1H), 7.62-7.57 (m, 1H), 7.44 (s, 1H), 6.27 (d, J=0.7 Hz, 1H).

165B. Preparation of(9R,13S)-13-{4-[5-chloro-2-(4-hydroxy-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-ihydropyrimidin-1-yl)}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate

(9R,13S)-13-{4-[5-Chloro-2-(4-hydroxy-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-ihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate (1.42 mg, 4.9% yield) was prepared in a similar manneras the procedure described in Example 162, using6-(5-chloro-2-(4-hydroxy-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol(0.012 g, 0.041 mmol) and(9R,13S)-13-amino-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(0.012 g, 0.041 mmol) prepared as described in Intermediate 32. MS(ESI)m/z: 572.3 (M+H)⁺. ¹H NMR (500 MHz, CD₃OD) δ 8.88 (s, 1H), 8.72 (d,J=5.2 Hz, 1H), 7.87 (d, J=2.2 Hz, 1H), 7.71-7.68 (m, 2H), 7.59 (d, J=8.5Hz, 1H), 7.52 (dd, J=5.2, 1.7 Hz, 1H), 7.49 (s, 1H), 7.43 (s, 1H), 6.22(d, J=0.8 Hz, 1H), 5.98 (dd, J=12.7, 4.1 Hz, 1H), 4.05 (s, 3H),2.75-2.66 (m, 1H), 2.36-2.25 (m, 1H), 2.11-1.96 (m, 2H), 1.65-1.55 (m,1H), 1.52-1.41 (m, 1H), 1.00 (d, J=6.9 Hz, 3H), 0.75-0.61 (m, 1H).Analytical HPLC (Method A): RT=6.12 min, 97.7% purity; Factor XIa Ki=13nM, Plasma Kallikrein Ki=750 nM.

Example 166 Preparation of5-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)pyridine-3-carbonitrile

5-(4-Chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)pyridine-3-carbonitrile,2 trifluoroacetate (1.5 mg, 5% yield) was prepared in a similar manneras the procedure described in Example 161, by replacingpyridin-3-ylboronic acid (4.76 mg, 0.039 mmol) with(5-cyanopyridin-3-yl)boronic acid (5.73 mg, 0.039 mmol). MS(ESI) m/z:591.2 (M+H)⁺. ¹H NMR (500 MHz, CD₃OD) δ 8.84 (d, J=1.9 Hz, 1H), 8.79 (s,1H), 8.72 (d, J=5.2 Hz, 1H), 8.64 (d, J=2.2 Hz, 1H), 8.08 (t, J=2.1 Hz,1H), 7.75 (d, J=2.2 Hz, 1H), 7.67-7.62 (m, 2H), 7.54-7.47 (m, 3H), 6.43(d, J=0.8 Hz, 1H), 6.00-5.94 (m, 1H), 4.04 (s, 3H), 2.74-2.66 (m, 1H),2.31-2.23 (m, 1H), 2.11-1.94 (m, 2H), 1.64-1.54 (m, 1H), 1.51-1.42 (m,1H), 1.00 (d, J=6.9 Hz, 3H), 0.75-0.60 (m, 1H). Analytical HPLC (MethodA): RT=6.86 min, 99.5% purity; Factor XIa Ki=58 nM, Plasma KallikreinKi=6,500 nM.

Example 167 Preparation of(9R,13S)-13-{4-[5-chloro-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate

(9R,13S)-13-{4-[5-Chloro-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate (3.96 mg, 9.6% yield) was prepared in a similar manneras the procedure described in Example 162, using6-(5-chloro-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-olhydrobromide (0.022 g, 0.057 mmol), prepared as described inIntermediate 13 and(9R,13S)-13-amino-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(0.017 g, 0.057 mmol) prepared as described in Intermediate 32. MS(ESI)m/z: 596.1 (M+H)⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.85 (s, 1H), 8.72 (d,J=5.1 Hz, 1H), 7.88-7.86 (m, 2H), 7.72-7.67 (m, 2H), 7.59 (d, J=8.6 Hz,1H), 7.51 (dd, J=5.1, 1.5 Hz, 1H), 7.49 (s, 1H), 6.17 (d, J=0.9 Hz, 1H),5.98 (dd, J=12.7, 4.3 Hz, 1H), 4.04 (s, 3H), 2.75-2.66 (m, 1H),2.34-2.24 (m, 1H), 2.12-1.93 (m, 3H), 1.66-1.40 (m, 2H), 1.03-0.94 (m,5H), 0.81-0.58 (m, 3H). Analytical HPLC (Method A): RT=7.43 min, 98.0%purity; Factor XIa Ki=3.2 nM, Plasma Kallikrein Ki=210 nM.

Example 168 Preparation of methyl4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}benzoate

168A. Preparation of methyl4-chloro-2-(6-methoxypyrimidin-4-yl)benzoate, and 168B. Preparation4-chloro-2-(6-methoxypyrimidin-4-yl)benzoic acid

A suspension of 4-chloro-6-methoxypyrimidine (0.067 g, 0.466 mmol) and(5-chloro-2-(methoxycarbonyl)phenyl)boronic acid (0.1 g, 0.466 mmol) inACN (1.8 ml) was purged with Ar for several min, then 2 M Na₂CO₃ aq(0.47 ml, 0.94 mmol) was added, followed by Pd(Ph₃P)₄ (0.027 g, 0.023mmol). The vial was capped and microwaved at 130° C. for 0.5 h, thencooled to rt. The reaction was diluted with EtOAc, washed with brine,dried over Na₂SO₄, filtered, and concentrated. Purification by normalphase chromatography afforded methyl4-chloro-2-(6-methoxypyrimidin-4-yl)benzoate (0.086 g, 66% yield) as acolorless oil. MS(ESI) m/z: 279.0 (M+H)⁺. The aqueous layer from thework-up was neutralized with 1 N HCl to afford a white cloudysuspension. The mixture was filtered, and the solid was rinsed withwater and air-dried to afford4-chloro-2-(6-methoxypyrimidin-4-yl)benzoic acid (0.026 g, 21% yield) asa white solid. MS(ESI) m/z: 265.0 (M+H)⁺.

168C. Preparation of methyl 4-chloro-2-(6-hydroxypyrimidin-4-yl)benzoate

Methyl 4-chloro-2-(6-hydroxypyrimidin-4-yl)benzoate (0.046 g, 56% yield)was prepared in a similar manner as the procedure described in Example140B, by replacing4-(5-chloro-2-(1-(difluoromethyl)-1H-pyrazol-4-yl)phenyl)-6-methoxypyrimidinewith methyl 4-chloro-2-(6-methoxypyrimidin-4-yl)benzoate (0.086 g, 0.309mmol). MS(ESI) m/z: 265.1 (M+H)⁺. ¹H NMR (500 MHz, CD₃OD) δ 8.19 (d,J=1.1 Hz, 1H), 7.83 (d, J=8.3 Hz, 1H), 7.62-7.57 (m, 2H), 6.57 (d, J=0.8Hz, 1H), 3.76 (s, 3H).

168D. Preparation of methyl4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}benzoatetrifluoroacetate

Methyl4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}benzoatetrifluoroacetate (0.067 g, 58% yield) was prepared in a similar manneras the procedure described in Example 56, by using methyl4-chloro-2-(6-hydroxypyrimidin-4-yl)benzoate (0.046 g, 0.174 mmol),prepared as described in Example 168C. MS(ESI) m/z: 547.2 (M+H)⁺. ¹H NMR(500 MHz, CD₃OD) δ 8.99 (s, 1H), 8.74 (d, J=5.2 Hz, 1H), 7.83 (d, J=8.3Hz, 1H), 7.75 (s, 1H), 7.62 (d, J=1.9 Hz, 1H), 7.59 (dd, J=8.3, 2.2 Hz,1H), 7.55 (dd, J=5.2, 1.7 Hz, 1H), 7.50 (s, 1H), 6.62 (s, 1H), 6.07 (dd,J=12.7, 4.1 Hz, 1H), 4.05 (s, 3H), 3.75 (s, 3H), 2.76-2.68 (m, 1H),2.41-2.33 (m, 1H), 2.14-2.03 (m, 2H), 1.67-1.58 (m, 1H), 1.55-1.45 (m,1H), 1.02 (d, J=6.9 Hz, 3H), 0.79-0.66 (m, 1H). Analytical HPLC (MethodA): RT=6.69 min, 99.9% purity; Factor XIa Ki=27 nM, Plasma KallikreinKi=650 nM.

Example 169 Preparation of(9R,13S)-13-{4-[3-chloro-6-(4-ethoxy-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate

(9R,13S)-13-{4-[3-Chloro-6-(4-ethoxy-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate (22 mg, 41.7% yield) was prepared in a similar manneras the procedure described in Example 162, using6-(3-chloro-6-(4-ethoxy-1H-1,2,3-triazol-1-yl)-2-fluorophenyl)pyrimidin-4-ol,hydrobromide (0.030 g, 0.072 mmol) and(9R,13S)-13-amino-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(0.025 g, 0.072 mmol) prepared as described in Intermediate 32. MS(ESI)m/z: 618.4 (M+H)⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.87 (s, 1H), 8.73 (d,J=5.1 Hz, 1H), 7.82 (t, J=8.1 Hz, 1H), 7.71 (s, 1H), 7.66 (s, 1H),7.56-7.47 (m, 3H), 6.54 (s, 1H), 6.00 (dd, J=12.5, 4.0 Hz, 1H), 4.13 (q,J=7.0 Hz, 2H), 4.05 (s, 3H), 2.76-2.65 (m, 1H), 2.36-2.24 (m, 1H),2.14-1.95 (m, 2H), 1.67-1.54 (m, 1H), 1.53-1.41 (m, 1H), 1.35 (t, J=7.0Hz, 3H), 1.00 (d, J=6.8 Hz, 3H), 0.77-0.59 (m, 1H). ¹⁹F NMR (376 MHz,CD₃OD) δ −77.75 (s), −115.15 (s). Analytical HPLC (Method A): RT=7.32min, 99.7% purity; Factor XIa Ki=0.88 nM, Plasma Kallikrein Ki=95 nM.

Example 170 Preparation of(9R,13S)-13-{4-[3-chloro-6-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate

(9R,13S)-13-{4-[3-Chloro-6-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate (0.02 g, 42.8% yield) was prepared in a similar manneras the procedure described in Example 160, by using6-(3-chloro-6-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-2-fluorophenyl)pyrimidin-4-ol(0.021 g, 0.063 mmol), prepared as described in Intermediate 14, and(9R,13S)-13-amino-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one (0.022 g, 0.063 mmol) prepared asdescribed in Intermediate 32. MS(ESI) m/z: 614.4 (M+H)⁺. ¹H NMR (400MHz, CD₃OD) δ 8.85 (s, 1H), 8.74 (d, J=5.1 Hz, 1H), 7.88-7.78 (m, 2H),7.71 (s, 1H), 7.57-7.47 (m, 3H), 6.51 (s, 1H), 6.00 (dd, J=12.7, 4.1 Hz,1H), 4.05 (s, 3H), 2.76-2.65 (m, 1H), 2.37-2.24 (m, 1H), 2.14-1.89 (m,3H), 1.67-1.39 (m, 2H), 1.05-0.90 (m, 5H), 0.77-0.60 (m, 3H). ¹⁹F NMR(376 MHz, CD₃OD) δ −77.75 (s), −115.19 (s). Analytical HPLC (Method A):RT=7.35 min, 99.2% purity; Factor XIa K_(i)=0.93 nM, Plasma KallikreinKi=95 nM.

Example 171 Preparation of(9R,13S)-13-{4-[3-chloro-2-fluoro-6-(trifluoromethyl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate

(9R,13S)-13-{4-[3-Chloro-2-fluoro-6-(trifluoromethyl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate (0.016 g, 40.1% yield) was prepared in a similar manneras the procedure described in Example 162, using6-(3-chloro-2-fluoro-6-(trifluoromethyl)phenyl)pyrimidin-4-olhydrobromide (0.021 g, 0.057 mmol) and

(9R,13S)-13-amino-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(0.02 g, 0.057 mmol) prepared as described in Intermediate 32. MS(ESI)m/z: 575.3 (M+H)⁺. ¹H NMR (400 MHz, CD₃OD) δ 9.05 (s, 1H), 8.77 (d,J=5.1 Hz, 1H), 7.85-7.79 (m, 1H), 7.75 (s, 1H), 7.66 (d, J=8.6 Hz, 1H),7.55 (dd, J=5.3, 1.5 Hz, 1H), 7.50 (s, 1H), 6.60 (s, 1H), 6.08 (dd,J=12.7, 4.3 Hz, 1H), 4.06 (s, 3H), 2.77-2.67 (m, 1H), 2.45-2.34 (m, 1H),2.16-2.04 (m, 2H), 1.70-1.44 (m, 2H), 1.02 (d, J=7.0 Hz, 3H), 0.81-0.64(m, 1H). ¹⁹F NMR (376 MHz, CD₃OD) δ −59.04 (s), −77.76 (s), −115.37 (s).Analytical HPLC (Method A): RT=8.30 min, 99.3% purity; Factor XIa Ki=12nM, Plasma Kallikrein Ki=190 nM.

Example 172 Preparation of(9R,13S)-13-{4-[3-chloro-6-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(²H₃)methyl-9-methyl-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

(9R,13S)-13-{4-[3-Chloro-6-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(²H₃)methyl-9-methyl-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(5.4 mg, 22.0% yield) was prepared in a similar manner as the proceduredescribed in Example 160, using6-(3-chloro-6-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-2-fluorophenyl)pyrimidin-4-ol(0.013 g, 0.040 mmol), prepared as described in Intermediate 14, and(9R,13S)-13-amino-3-(²H₃)methyl-9-methyl-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(0.012 g, 0.040 mmol), prepared as described in Intermediate 36. MS(ESI)m/z: 616.3 (M+H)⁺. ¹H NMR (400 MHz, CD₃₀OD) δ 8.17 (s, 1H), 7.84-7.73(m, 3H), 7.62-7.54 (m, 2H), 7.50-7.46 (m, 2H), 7.32 (d, J=7.5 Hz, 1H),6.55 (s, 1H), 5.82 (dd, J=12.8, 3.1 Hz, 1H), 2.52-2.42 (m, 1H),2.38-2.27 (m, 1H), 2.15-2.03 (m, 1H), 1.97-1.81 (m, 2H), 1.62-1.49 (m,2H), 1.26-1.10 (m, 4H), 1.00-0.90 (m, 2H), 0.73-0.63 (m, 2H). AnalyticalHPLC (Method A): RT=8.18 min, 100% purity; Factor XIa Ki=0.36 nM, PlasmaKallikrein Ki=45 nM.

Example 173 Preparation of(9R,13S)-13-(4-{3-chloro-2-fluoro-6-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate

(9R,13S)-13-(4-{3-Chloro-2-fluoro-6-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate (0.0215 g, 56.3% yield) was prepared in a similarmanner as the procedure described in Example 160, using6-(3-chloro-2-fluoro-6-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol(0.018 g, 0.050 mmol), prepared as described in Intermediate 11, and(9R,13S)-13-amino-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(0.015 g, 0.050 mmol) prepared as described in Intermediate 32. MS(ESI)m/z: 642.3 (M+H)⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.82 (s, 1H), 8.78 (s, 1H),8.70 (d, J=5.1 Hz, 1H), 7.91-7.83 (m, 1H), 7.70 (s, 1H), 7.59 (dd,J=8.6, 1.3 Hz, 1H), 7.53 (dd, J=5.2, 1.4 Hz, 1H), 7.48 (s, 1H), 6.65 (s,1H), 6.00 (dd, J=12.7, 4.1 Hz, 1H), 4.05 (s, 3H), 2.74-2.64 (m, 1H),2.33-2.22 (m, 1H), 2.12-1.93 (m, 2H), 1.66-1.39 (m, 2H), 1.00 (d, J=7.0Hz, 3H), 0.75-0.58 (m, 1H). ¹⁹F NMR (376 MHz, CD₃OD) δ −62.57 (s),−77.74 (s), −114.95 (s). Analytical HPLC (Method A): RT=8.64 min, 99.6%purity; Factor XIa Ki=0.11 nM, Plasma Kallikrein Ki=13 nM.

Example 174 Preparation of1-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}-3-fluorophenyl)-1H-1,2,3-triazole-4-carbonitriletrifluoroacetate

1-(4-Chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}-3-fluorophenyl)-1H-1,2,3-triazole-4-carbonitriletrifluoroacetate (0.0105 g, 0.015 mmol, 23.13% yield) was prepared in asimilar manner as the procedure described in Example 160, using1-(4-chloro-3-fluoro-2-(6-hydroxypyrimidin-4-yl)phenyl)-1H-1,2,3-triazole-4-carbonitrile(0.02 g, 0.063 mmol), prepared as described in Intermediate 12, and(9R,13S)-13-amino-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(0.019 g, 0.063 mmol) prepared as described in Intermediate 32. MS(ESI)m/z: 599.2 (M+H)⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.93 (s, 1H), 8.78-8.74 (m,2H), 7.93-7.86 (m, 1H), 7.70 (s, 1H), 7.60 (dd, J=8.7, 1.4 Hz, 1H), 7.53(dd, J=5.1, 1.5 Hz, 1H), 7.49 (s, 1H), 6.65 (s, 1H), 5.99 (dd, J=12.4,3.6 Hz, 1H), 4.05 (s, 3H), 2.75-2.65 (m, 1H), 2.35-2.23 (m, 1H),2.13-1.95 (m, 2H), 1.67-1.41 (m, 2H), 1.01 (d, J=6.8 Hz, 3H), 0.78-0.60(m, 1H). ¹⁹F NMR (376 MHz, CD₃OD) δ −77.72 (s), −114.94 (s). AnalyticalHPLC (Method A): RT=7.85 min, 99.2% purity; Factor XIa Ki=0.1 nM, PlasmaKallikrein Ki=6 nM.

Example 175 Preparation of(9R,13S)-13-(4-{3-chloro-2-fluoro-6-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(²H₃)methyl-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate

(9R,13S)-13-(4-{3-Chloro-2-fluoro-6-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(²H₃)methyl-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate (0.018 g, 44.8% yield) was prepared in a similar manneras the procedure described in Example 160, using6-(3-chloro-2-fluoro-6-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol(0.019 g, 0.053 mmol), prepared as described in Intermediate 11, and(9R,13S)-13-amino-3-(²H₃)methyl-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(0.016 g, 0.053 mmol) prepared as described in Intermediate 33. MS(ESI)m/z: 645.3 (M+H)⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.81 (d, J=0.7 Hz, 1H),8.78 (s, 1H), 8.71 (d, J=5.1 Hz, 1H), 7.87 (dd, J=8.6, 7.7 Hz, 1H), 7.70(s, 1H), 7.59 (dd, J=8.7, 1.4 Hz, 1H), 7.53 (dd, J=5.1, 1.5 Hz, 1H),7.49 (s, 1H), 6.64 (s, 1H), 6.00 (dd, J=12.7, 4.3 Hz, 1H), 2.75-2.65 (m,1H), 2.33-2.22 (m, 1H), 2.12-1.92 (m, 2H), 1.66-1.40 (m, 2H), 1.00 (d,J=6.8 Hz, 3H), 0.78-0.60 (m, 1H). ¹⁹F NMR (376 MHz, CD₃OD) δ −62.59 (s),−77.76 (s), −114.95 (s). Analytical HPLC (Method A): RT=8.44 min, 100%purity; Factor XIa Ki=0.11 nM, Plasma Kallikrein Ki=12 nM.

Example 176 Preparation of1-(4-chloro-2-{1-[(9R,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}-3-fluorophenyl)-1H-1,2,3-triazole-4-carbonitriletrifluoroacetate

1-(4-Chloro-2-{1-[(9R,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}-3-fluorophenyl)-1H-1,2,3-triazole-4-carbonitriletrifluoroacetate (9 mg, 20.1% yield) was prepared in a similar manner asthe procedure described in Example 160, using1-(4-chloro-3-fluoro-2-(6-hydroxypyrimidin-4-yl)phenyl)-1H-1,2,3-triazole-4-carbonitrile(18.89 mg, 0.060 mmol), prepared as described in Intermediate 12, and(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(20 mg, 0.060 mmol) prepared as described in Intermediate 30. MS(ESI)m/z: 635.2 (M+H)⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.92 (s, 1H), 8.81 (s, 1H),8.77 (d, J=5.3 Hz, 1H), 7.92-7.85 (m, 1H), 7.81-7.48 (m, 5H), 6.65 (s,1H), 6.00 (dd, J=12.7, 4.5 Hz, 1H), 2.76-2.65 (m, 1H), 2.34-2.22 (m,1H), 2.10-1.95 (m, 2H), 1.64-1.41 (m, 2H), 0.99 (d, J=6.8 Hz, 3H),0.73-0.55 (m, 1H). ¹⁹F NMR (376 MHz, CD₃OD) δ −77.28 (s), −90.87-−92.15(m), −96.05-−97.42 (m), −114.86 (s). Analytical HPLC (Method A): RT=9.02min, 99.6% purity; Factor XIa Ki=0.1 nM, Plasma Kallikrein Ki=7 nM.

Example 177 Preparation of(9R,13S)-13-{4-[3-chloro-6-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate

(9R,13S)-13-{4-[3-Chloro-6-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-6-oxo-1,6-dihydropyrimidin-1-yl)}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate (7.07 mg, 20.6% yield) was prepared in a similar manneras the procedure described in Example 160, using6-(3-chloro-6-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-2-fluorophenyl)pyrimidin-4-ol (0.015 g, 0.045 mmol), prepared as described inIntermediate 14, and

(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(0.015 g, 0.045 mmol) prepared as described in Intermediate 30. MS(ESI)m/z: 650.5 (M+H)⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.92 (s, 1H), 8.76 (d,J=5.1 Hz, 1H), 7.86-7.47 (m, 7H), 6.50 (s, 1H), 6.04 (dd, J=12.5, 4.4Hz, 1H), 2.77-2.66 (m, 1H), 2.35-2.24 (m, 1H), 2.10-1.87 (m, 3H),1.66-1.41 (m, 2H), 1.02-0.89 (m, 5H), 0.73-0.50 (m, 3H). ¹⁹F NMR (376MHz, CD₃OD) δ −77.68 (s), −90.26-−91.77 (m), −95.81-−97.73 (m), −115.24(s). Analytical HPLC (Method A): RT=8.74 min, 99.8% purity; Factor XIaKi=0.50 nM, Plasma Kallikrein Ki=120 nM.

Example 178 Preparation of(9R,13S)-13-(4-{3-chloro-6-[4-(difluoromethyl)-1H-1,2,3-triazol-1-yl]-2-fluorophenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate

(9R,13S)-13-(4-{3-Chloro-6-[4-(difluoromethyl)-1H-1,2,3-triazol-1-yl]-2-fluorophenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate (0.016 g, 46.0% yield) was prepared in a similar manneras the procedure described in Example 160, using6-(3-chloro-6-(4-(difluoromethyl)-1H-1,2,3-triazol-1-yl)-2-fluorophenyl)pyrimidin-4-ol(0.015 g, 0.045 mmol), prepared as described in Intermediate 21, and(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(15 mg, 0.045 mmol), prepared as described in Intermediate 30. MS(ESI)m/z: 660.5 (M+H)⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.86 (s, 1H), 8.73 (d,J=5.1 Hz, 1H), 8.52 (t, J=1.4 Hz, 1H), 7.86 (dd, J=8.6, 7.5 Hz, 1H),7.80-7.48 (m, 5H), 6.96 (t, J=54.0 Hz, 1H), 6.60 (s, 1H), 6.02 (dd,J=12.5, 4.4 Hz, 1H), 2.76-2.66 (m, 1H), 2.32-2.20 (m, 1H), 2.09-1.92 (m,2H), 1.65-1.40 (m, 2H), 0.99 (d, J=7.0 Hz, 3H), 0.69-0.52 (m, 1H). ¹⁹FNMR (376 MHz, CD₃OD) δ −77.73 (s), −90.24-−92.35 (m), −95.39-−97.64 (m),−114.57 (d, J=10.3 Hz), −115.06 (s). Analytical HPLC (Method A): RT=8.91min, 99.6% purity; Factor XIa Ki=0.1 nM, Plasma Kallikrein Ki=16 nM.

Example 179 Preparation of(9R,13S)-13-(4-{3-chloro-6-[4-(difluoromethyl)-1H-1,2,3-triazol-1-yl]-2-fluorophenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate

(9R,13S)-13-(4-{3-Chloro-6-[4-(difluoromethyl)-1H-1,2,3-triazol-1-yl]-2-fluorophenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate (0.015 g, 43.3% yield) was prepared in a similar manneras the procedure described in Example 160, using6-(3-chloro-6-(4-(difluoromethyl)-1H-1,2,3-triazol-1-yl)-2-fluorophenyl)pyrimidin-4-ol(0.016 g, 0.047 mmol), prepared as described in Intermediate 21, and(9R,13S)-13-amino-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(0.014 g, 0.047 mmol) prepared as described in Intermediate 32. MS(ESI)m/z: 624.5 (M+H)⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.79 (s, 1H), 8.72 (d,J=5.1 Hz, 1H), 8.52 (t, J=1.3 Hz, 1H), 7.86 (dd, J=8.6, 7.7 Hz, 1H),7.70 (s, 1H), 7.59-7.51 (m, 2H), 7.48 (s, 1H), 6.97 (t, J=54.0 Hz, 1H),6.60 (s, 1H), 5.99 (dd, J=12.7, 4.3 Hz, 1H), 4.05 (s, 3H), 2.75-2.64 (m,1H), 2.34-2.21 (m, 1H), 2.12-1.93 (m, 2H), 1.66-1.39 (m, 2H), 1.00 (d,J=6.8 Hz, 3H), 0.78-0.59 (m, 1H). ¹⁹F NMR (376 MHz, CD₃OD) δ −77.74 (s),−114.52 (d, J=8.0 Hz), −115.03 (s). Analytical HPLC (Method A): RT=7.79min, 99.6% purity; Factor XIa Ki=0.14 nM, Plasma Kallikrein Ki=16 nM.

Example 180 Preparation of(9R,13S)-13-[4-(3-chlorophenyl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

(9R,13S)-13-[4-(3-Chlorophenyl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate (3.35 mg, 15% yield) was prepared in a similar manneras the procedure described in Example 161, by replacingpyridin-3-ylboronic acid (4.76 mg, 0.039 mmol) with lithium4-methyl-1-(1-methyl-1H-1,2,3-triazol-4-yl)-2,6,7-trioxa-1-borabicyclo[2.2.2]octan-1-uide(8.41 mg, 0.039 mmol). MS(ESI) m/z: 489.3 (M+H)⁺. ¹H NMR (500 MHz,CD₃OD) δ 9.01 (s, 1H), 8.73 (d, J=5.2 Hz, 1H), 8.08 (t, J=1.7 Hz, 1H),7.94 (dt, J=7.5, 1.6 Hz, 1H), 7.73 (s, 1H), 7.54-7.44 (m, 4H), 6.93 (d,J=0.5 Hz, 1H), 6.04 (dd, J=12.5, 4.0 Hz, 1H), 4.05 (s, 3H), 2.76-2.68(m, 1H), 2.42-2.32 (m, 1H), 2.15-2.02 (m, 2H), 1.67-1.57 (m, 1H),1.55-1.45 (m, 1H), 1.02 (d, J=6.9 Hz, 3H), 0.81-0.65 (m, 1H). AnalyticalHPLC (Method A): RT=7.33 min, 99.0% purity; Factor XIa Ki=360 nM, PlasmaKallikrein Ki=6,800 nM.

Example 181 Preparation of4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}benzoicacid

To the solution of methyl4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}benzoatetrifluoroacetate (0.02 g, 0.030 mmol), prepared as described in Example168, in DCM (0.5 ml) at 0° C. was added BBr₃ (0.029 ml, 0.30 mmol). Thereaction became a yellow suspension. After 10 min, the cold bath wasremoved, and the reaction was stirred at rt. After 18 h, the reactionwas cooled to 0° C. and carefully quenched with MeOH. The reaction waswarmed to rt and then concentrated. Purification by reverse phasechromatography afforded4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}benzoicacid trifluoroacetate (0.011 g, 56% yield) as a white solid. MS(ESI)m/z: 533.1 (M+H)⁺. ¹H NMR (400 MHz, CD₃OD) δ 9.00 (s, 1H), 8.74 (d,J=5.1 Hz, 1H), 7.90 (d, J=9.0 Hz, 1H), 7.73 (s, 1H), 7.61-7.56 (m, 2H),7.53 (dd, J=5.3, 1.5 Hz, 1H), 7.50 (s, 1H), 6.58 (s, 1H), 6.07 (dd,J=12.8, 4.2 Hz, 1H), 4.05 (s, 3H), 2.77-2.67 (m, 1H), 2.41-2.30 (m, 1H),2.16-2.00 (m, 2H), 1.68-1.57 (m, 1H), 1.55-1.43 (m, 1H), 1.01 (d, J=7.0Hz, 3H), 0.79-0.62 (m, 1H). Analytical HPLC (Method A): RT=5.54 min,99.9% purity; Factor XIa Ki=500 nM.

Example 182 Preparation of(9R,13S)-3-(difluoromethyl)-9-methyl-13-{6-oxo-4-[5-(propan-2-yl)-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl]-1,6-dihydropyrimidin-1-yl}-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

182A. Preparation of4-isopropyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline

4-Isopropyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1.21g, 99%) was prepared in a similar manner as Example 119A starting from2-bromo-4-isopropylaniline. MS(ESI) m/z: 180 (M-C₆H₁₀+H)⁺.

182B. Preparation 4-isopropyl-2-(6-methoxypyrimidin-4-yl)aniline

4-Isopropyl-2-(6-methoxypyrimidin-4-yl)aniline (511 mg, 46%) wasprepared in a similar manner as Example 119B using4-isopropyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline.MS(ESI) m/z: 244.1 (M+H)⁺.

182C. Preparation of4-(5-isopropyl-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-6-methoxypyrimidine

4-(5-Isopropyl-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-6-methoxypyrimidine(522 mg, 68%) was prepared in a similar manner as Example 119C using4-isopropyl-2-(6-methoxypyrimidin-4-yl)aniline. MS(ESI) m/z: 364.1(M+H)⁺.

182D. Preparation of6-(5-isopropyl-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol

6-(5-Isopropyl-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol(459 mg, 91%) was prepared in a similar manner as Example 119D using4-(5-isopropyl-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-6-methoxypyrimidine.MS(ESI) m/z: 350.1 (M+H)⁺. ¹H NMR (400 MHz, CDCl₃) δ 12.53 (br. s., 1H),8.06 (s, 1H), 7.92 (s, 1H), 7.58-7.50 (m, 2H), 7.47-7.44 (m, 1H), 6.54(s, 1H), 3.15-3.03 (m, 1H), 1.38-1.30 (m, 6H).

182E. Preparation of(9R,13S)-3-(difluoromethyl)-9-methyl-13-{6-oxo-4-[5-(propan-2-yl)-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl]-1,6-dihydropyrimidin-1-yl}-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one,trifluoroacetate

(9R,13S)-3-(Difluoromethyl)-9-methyl-13-{6-oxo-4-[5-(propan-2-yl)-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl]-1,6-dihydropyrimidin-1-yl}-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one,trifluoroacetate (1.6 mg, 3.4%) was prepared in a similar manner asExample 56 using6-(5-isopropyl-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol(21 mg, 0.060 mmol) and of(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(20 mg, 0.060 mmol), prepared as described in Intermediate 30. MS(ESI)m/z: 668.2 (M+H)⁺. ¹H NMR (500 MHz, DMSO-d6) δ 9.39 (s, 1H), 9.17 (s,1H), 8.76 (s, 1H), 8.70 (d, J=5.2 Hz, 1H), 8.09-7.94 (m, 1H), 7.91-7.80(m, 1H), 7.73-7.60 (m, 3H), 7.43 (d, J=4.7 Hz, 1H), 6.39 (s, 1H), 5.90(d, J=10.2 Hz, 1H), 3.09 (dt, J=13.9, 6.8 Hz, 1H), 2.64 (d, J=3.3 Hz,1H), 2.29 (t, J=12.7 Hz, 1H), 2.09-2.01 (m, 1H), 1.87-1.80 (m, 1H),1.52-1.43 (m, 1H), 1.30 (d, J=6.9 Hz, 5H), 0.87 (d, J=6.9 Hz, 2H), 0.37(br. s., 1H). Analytical HPLC (Method C): RT=2.00 min, 100% purity;Factor XIa Ki=500 nM.

Example 183 Preparation of(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(²H₃)methyl-9-methyl-3,4,7,17-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

(9R,13S)-13-(4-{5-Chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(²H₃)methyl-9-methyl-3,4,7,17-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(0.068 g, 18.7%) as a white solid, was prepared in a similar manner asthe procedure described in Example 56 by using6-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol(0.188 g, 0.549 mmol), as described in Intermediate 15, and(9R,13S)-13-amino-3-(²H₃)methyl-9-methyl-3,4,7,17-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one (0.166 g, 0.549 mmol), as described inIntermediate 34. MS(ESI) m/z: 627.5 (M+H)⁺. ¹H NMR (400 MHz, CD₃OD) δ8.84 (d, J=0.7 Hz, 1H), 8.72 (d, J=5.1 Hz, 1H), 8.29 (s, 1H), 7.91 (d,J=2.4 Hz, 1H), 7.86 (s, 1H), 7.82-7.76 (m, 1H), 7.74-7.69 (m, 1H), 7.51(s, 1H), 7.16 (dd, J=5.2, 1.7 Hz, 1H), 6.53 (d, J=0.9 Hz, 1H), 5.78 (dd,J=12.4, 3.0 Hz, 1H), 2.70-2.57 (m, 1H), 2.40 (d, J=12.8 Hz, 1H),2.15-2.08 (m, 1H), 2.04-1.94 (m, 1H), 1.64 (d, J=6.8 Hz, 1H), 1.48-1.32(m, 2H), 1.15 (d, J=6.8 Hz, 3H). Analytical HPLC (Method A) RT=8.04 min,purity=95%; Factor XIa Ki=0.15 nM, Plasma Kallikrein Ki=18 nM.

Example 184 Preparation of(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaene-16-carbonitrile

(9R,13S)-13-(4-{5-Chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaene-16-carbonitrile(8 mg, 13.5%) as a white solid, was prepared in a similar manner as(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaene-16-carbonitrile,as described in Example 130, by replacing6-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]pyrimidin-4-ol with6-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}pyrimidin-4-ol,as described in Intermediate 15. LCMS(ESI) m/z: 684.2 (M+H)⁺. ¹H NMR(400 MHz, CD₃OD) δ 8.82 (d, J=0.7 Hz, 1H), 8.32 (s, 1H), 8.03 (s, 1H),7.90 (d, J=2.4 Hz, 2H), 7.83-7.75 (m, 3H), 7.73-7.43 (m, 2H), 6.48 (d,J=0.4 Hz, 1H), 5.76 (dd, J=13.1, 3.4 Hz, 1H), 2.60-2.42 (m, 2H),2.17-2.05 (m, 1H), 1.88 (dt, J=7.2, 3.7 Hz, 1H), 1.64-1.53 (m, 1H), 1.42(d, J=8.1 Hz, 1H), 1.20 (br. s., 1H), 1.13 (d, J=6.8 Hz, 3H). AnalyticalHPLC (Method A) RT=9.31 min, purity=98%; Factor XIa Ki=0.10 nM, PlasmaKallikrein Ki=15 nM.

Example 185 Preparation of(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,17-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

(9R,13S)-13-(4-{5-Chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,17-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(0.16 g, 27%), as a white solid, was prepared in a similar manner asExample 56, using6-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol(0.308 g, 0.902 mmol), as described in Intermediate 15, and(9R,13S)-13-amino-3,9-dimethyl-3,4,7,17-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(0.27 g, 0.902 mmol), as described in Intermediate 42. LCMS(ESI) m/z:624.5 (M+H)⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.84 (d, J=0.9 Hz, 1H), 8.71 (d,J=5.5 Hz, 1H), 8.29 (s, 1H), 7.91 (d, J=2.2 Hz, 1H), 7.86 (s, 1H),7.80-7.75 (m, 1H), 7.73-7.70 (m, 1H), 7.51 (s, 1H), 7.16 (dd, J=5.2, 1.7Hz, 1H), 6.53 (d, J=0.7 Hz, 1H), 5.78 (dd, J=12.5, 3.1 Hz, 1H), 4.18 (s,3H), 2.69-2.55 (m, 1H), 2.40 (d, J=11.9 Hz, 1H), 2.11 (dd, J=13.3, 3.6Hz, 1H), 2.00 (dd, J=14.0, 3.6 Hz, 1H), 1.64 (d, J=7.0 Hz, 1H),1.50-1.29 (m, 2H), 1.15 (d, J=6.8 Hz, 3H). Analytical HPLC (Method A)RT=8.07 min, purity=95%; Factor XIa Ki=0.14 nM, Plasma Kallikrein Ki=18nM.

Example 186 Preparation of(9S,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-10-fluoro-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate

186A. Preparation of tert-butylN-[(9S,13S)-10-fluoro-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate

Fe₂(C₂O₄)₃.6H₂O (1.910 g, 3.95 mmol) was dissolved in water (75 mL) thenpurged with Ar (3×). SELECTFLUOR® (1398 mg, 3.95 mmol) was added,followed by tert-butylN-[(9R,10E,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate,prepared as described in Intermediate 32E (523 mg, 1.32 mmol), in ACN(75 mL). NaBH₄ (398 mg, 10.53 mmol) was added portionwise and thesolution was stirred at rt for 1 h. The reaction mixture was quenchedwith 30% aq NH₄OH (40 ml), extracted with 500 ml 10% MeOH in DCM. Thecombined organic extracts were washed with brine, dried over MgSO₄,filtered, concentrated. The residue was purified by reverse phasechromatography to give a mixture of tert-butylN-[(9S,13S)-10-fluoro-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamateand tert-butylN-[(9R,13S)-11-fluoro-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate(130 mg) as a solid. Further purification with chiral reverse phasechromatography gave tert-butylN-[(9S,13S)-10-fluoro-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate(59 mg, 10% yield) as a single isomer as a white solid.

186B. Preparation of(9S,13S)-13-amino-10-fluoro-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

To a solution of tert-butylN-[(9S,13S)-10-fluoro-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate(96 mg, 0.230 mmol) in DCM (2 mL) was added TFA (0.709 mL, 9.20 mmol).The reaction mixture was stirred at rt for 2 h, then was concentrated togive(9S,13S)-13-amino-10-fluoro-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate as a pale yellow solid, which was then dissolved inMeOH, passed through PL-HCO₃ MP SPE 500 mg per 6 ml tube, and rinsedwith MeOH, The filtrate was concentrated to give(9S,13S)-13-amino-10-fluoro-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(72 mg, 99% yield). MS(ESI) m/z: 318.08 (M+H)⁺.

186C. Preparation of(9S,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-10-fluoro-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate

((9S,13S)-13-{4-[5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-10-fluoro-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one)trifluoroacetate (7.7 mg, 39% yield) was prepared in a similar manner asthe procedure described in Example 184, by replacing methyl(10R,14S)-14-amino-10-methyl-9-oxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaene-4-carboxylatewith(9S,13S)-13-amino-10-fluoro-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one.MS(ESI) m/z: 608.08 (M+H)⁺. ¹H NMR (400 MHz, CD₃OD) δ 9.10 (s, 1H), 8.77(d, J=5.3 Hz, 1H), 8.36 (s, 1H), 7.91 (d, J=2.4 Hz, 1H), 7.78-7.73 (m,1H), 7.69-7.64 (m, 1H), 7.56 (d, J=0.9 Hz, 1H), 7.53-7.46 (m, 2H), 6.39(d, J=0.7 Hz, 1H), 6.25 (dd, J=12.1, 5.9 Hz, 1H), 5.46-5.23 (m, 1H),4.05 (s, 3H), 3.22-3.11 (m, 1H), 2.36-2.19 (m, 2H), 1.86-1.68 (m, 1H),1.00 (d, J=6.8 Hz, 3H), 0.75-0.51 (m, 1H) Analytical HPLC (Method A):RT=8.33 min, purity=>97%; Factor XIa Ki=0.37 nM, Plasma Kallikrein Ki=30nM.

Example 187 Preparation of(9R,13S)-3-(difluoromethyl)-13-(4-{5-ethyl-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

187A. Preparation of4-ethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline

4-Ethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.638 g,52%) was prepared in a similar manner as Example 119A starting from2-bromo-4-ethylaniline. MS(ESI) m/z: 166.0 (M-C₆H₁₀+H)⁺. ¹H NMR (400MHz, chloroform-d) δ 7.44 (d, J=2.2 Hz, 1H), 7.08 (dd, J=8.3, 2.3 Hz,1H), 6.57 (d, J=8.4 Hz, 1H), 4.60 (br. s., 2H), 1.38-1.33 (m, 12H), 1.27(s, 2H), 1.21-1.16 (m, 3H).

187B. Preparation 4-ethyl-2-(6-methoxypyrimidin-4-yl)aniline

4-Ethyl-2-(6-methoxypyrimidin-4-yl)aniline (611 mg, 60%) was prepared ina similar manner as Example 119B using4-ethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline. MS(ESI)m/z: 230.1 (M+H)⁺.

187C. Preparation of4-(5-ethyl-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-6-methoxypyrimidine

4-(5-Ethyl-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-6-methoxypyrimidine(430 mg, 46%) was prepared in a similar manner as Example 119C using4-ethyl-2-(6-methoxypyrimidin-4-yl)aniline. MS(ESI) m/z: 350.1 (M+H)⁺.

187D. Preparation of6-(5-isopropyl-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol

6-(5-Ethyl-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol(345 mg, 84%) was prepared in a similar manner as Example 119D using4-(5-ethyl-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-6-methoxypyrimidine.MS(ESI) m/z: 336.1 (M+H)⁺. ¹H NMR (400 MHz, CDCl₃) δ 12.80 (br. s., 1H),8.06 (s, 1H), 7.93 (s, 1H), 7.59-7.41 (m, 3H), 6.53 (s, 1H), 2.83 (q,J=7.7 Hz, 2H), 1.34 (t, J=7.6 Hz, 3H).

187E. Preparation of(9R,13S)-3-(difluoromethyl)-13-(4-{5-ethyl-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate

(9R,13S)-3-(Difluoromethyl)-13-(4-{5-ethyl-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate (0.9 mg, 2.0%) was prepared in a similar manner asExample 56 using6-(5-ethyl-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol(21 mg, 0.060 mmol) and(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(20 mg, 0.060 mmol), prepared as described in Intermediate 30. MS(ESI)m/z: 654.2 (M+H)⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 9.40 (s, 1H), 9.18 (s,1H), 8.78-8.65 (m, 2H), 8.09-7.93 (m, 1H), 7.90-7.83 (m, 1H), 7.72-7.65(m, 3H), 7.59 (dd, J=8.2, 1.5 Hz, 1H), 7.43 (d, J=4.9 Hz, 1H), 6.38 (s,1H), 5.90 (d, J=9.5 Hz, 1H), 2.79 (q, J=7.4 Hz, 2H), 2.69-2.61 (m, 1H),2.28 (t, J=12.5 Hz, 1H), 2.09-2.00 (m, 1H), 1.89-1.79 (m, 1H), 1.47 (dt,J=12.2, 6.4 Hz, 1H), 1.38-1.23 (m, 4H), 0.88 (d, J=6.7 Hz, 3H), 0.36(br. s., 1H). Analytical HPLC (Method C): RT=1.896 min, 100% purity;Factor XIa Ki=110 nM.

Example 188 Preparation of(9S,13S)-13-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-10-fluoro-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate

(9S,13S)-13-{4-[3-Chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-10-fluoro-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(9.33 mg, 32% yield) was prepared in a similar manner as the proceduredescribed in Example 186 by replacing6-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]pyrimidin-4-ol with6-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]pyrimidin-4-ol,prepared as described in Intermediate 10. MS(ESI) m/z: 626.1 (M+H)⁺. ¹HNMR (400 MHz, CD₃OD) δ 9.10 (s, 1H), 8.78 (d, J=5.1 Hz, 1H), 8.34 (s,1H), 7.88 (dd, J=8.7, 7.6 Hz, 1H), 7.60-7.54 (m, 2H), 7.53-7.48 (m, 2H),6.63 (s, 1H), 6.27 (dd, J=11.8, 6.3 Hz, 1H), 5.44-5.25 (m, 1H), 4.05 (s,3H), 3.23-3.12 (m, 1H), 2.35-2.21 (m, 2H), 1.85-1.69 (m, 1H), 1.00 (d,J=6.8 Hz, 3H), 0.75-0.52 (m, 1H). Analytical HPLC (Method A): RT=8.41min, purity=>99%; Factor XIa Ki=0.15 nM, Plasma Kallikrein Ki=19 nM.

Example 189 Preparation of(9R,13S)-13-{5-chloro-4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate

189A. Preparation of5-chloro-6-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]pyrimidin-4-ol

To a solution of6-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol (100mg, 0.325 mmol), prepared as described in Intermediate 9, in ACN (3.24mL) was added Palau'chlor (82 mg, 0.389 mmol). The reaction was stirredat 60° C. for 4 h and then the reaction was cooled to rt andconcentrated. Purification by normal phase chromatography, usingEtOAc/Hex, gave a white solid weighing 0.135 g. Purification by reversephase chromatography, gave a white solid. The solid was partitionedbetween sat NaHCO₃ and EtOAc and the layers were separated. The aqueouslayer was extracted with EtOAc. The organic layers were combined, driedover MgSO₄, filtered and concentrated to give5-chloro-6-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]pyrimidin-4-ol(63 mg, 57%) as a beige solid. MS(ESI) m/z: 342 (M+H)⁺, 344.1 (M+2+H)⁺,and 346.0 (M+4+H)⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.09 (s, 1H), 7.75 (s,1H), 7.66-7.61 (m, 2H), 7.55-7.50 (m, 1H).

189B. Preparation of(9R,13S)-13-{5-chloro-4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate

(9R,13S)-13-{5-Chloro-4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate (0.0071 g, 23%) was prepared in a similar manner as theprocedure described in Example 56, by replacing6-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}pyrimidin-4-olwith5-chloro-6-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]pyrimidin-4-ol.MS(ESI) m/z: 624 (M+H)⁺, 626.3 (M+2+H)⁺, and 628.2 (M+4+H)⁺. ¹H NMR (500MHz, DMSO-d₆) δ 9.15 (s, 1H), 8.83 (s, 1H), 8.75 (s, 1H), 8.63 (d, J=5.0Hz, 1H), 7.83-7.73 (m, 3H), 7.62 (s, 1H), 7.53 (dd, J=5.1, 1.5 Hz, 1H),7.40 (s, 1H), 5.88-5.78 (m, 1H), 3.95 (s, 3H), 2.62-2.52 (m, 1H),2.32-2.21 (m, 1H), 2.08-1.98 (m, 1H), 1.87-1.78 (m, 1H), 1.47-1.36 (m,1H), 1.33-1.21 (m, 1H), 0.81 (d, J=6.9 Hz, 3H), 0.45-0.29 (m, 1H).Analytical HPLC (Method A): RT=8.03 min, purity=99.5%; Factor XIaKi=0.46 nM, Plasma Kallikrein Ki=29 nM.

Example 190 Preparation of(9R,13S)-3-(difluoromethyl)-13-(4-{4-fluoro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

(9R,13S)-3-(Difluoromethyl)-13-(4-{4-fluoro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onewas prepared (0.72 mg, 6% yield as a solid via the coupling of6-{4-fluoro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}pyrimidin-4-ol(0.006 g, 0.018 mmol) and(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one (0.006 g, 0.018 mmol) using the HATU, DBU couplingmethodology as described in Example 56. LCMS m/z=644.2 (M+H)⁺. ¹H NMR(400 MHz, CD₃OD) δ 8.83-8.77 (m, 2H), 8.73-8.69 (m, 1H), 7.91-7.86 (m,1H), 7.75-7.72 (m, 2H), 7.68-7.49 (m, 4H), 6.05-5.96 (m, 1H), 2.75-2.62(m, 1H), 2.30-2.18 (m, 1H), 2.05-1.94 (m, 2H), 1.64-1.36 (d, 3H),1.02-0.94 (m, 1H). Analytical HPLC (Method A) RT=8.75 min, purity=98%;Factor XIa Ki=110 nM.

Example 191 Preparation of(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(²H₃)methyl-9-methyl-3,4,7,17-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

(9R,13S)-13-{4-[5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(²H₃)methyl-9-methyl-3,4,7,17-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(10.8 mg, 18.4%), as a white solid, was prepared in a similar manner asExample 56, using6-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]pyrimidin-4-ol(0.024 g, 0.079 mmol), as described in Intermediate 9, and(9R,13S)-13-amino-3-(²H₃)methyl-9-methyl-3,4,7,17-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(0.024 g, 0.079 mmol), as described in Intermediate 34. LCMS(ESI) m/z:593.3 (M+H)⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.78-8.69 (m, 1H), 8.42-8.33 (m,2H), 7.92-7.86 (m, 2H), 7.80-7.74 (m, 1H), 7.69-7.64 (m, 1H), 7.52 (s,1H), 7.21 (dd, J=5.3, 1.5 Hz, 1H), 6.51-6.43 (m, 1H), 5.77 (dd, J=12.5,3.3 Hz, 1H), 2.62 (ddd, J=9.5, 6.7, 3.4 Hz, 1H), 2.48-2.38 (m, 1H),2.22-2.11 (m, 1H), 2.06-1.97 (m, 1H), 1.69-1.59 (m, 1H), 1.42-1.33 (m,2H), 1.15 (d, J=6.8 Hz, 3H). Analytical HPLC (Method A) RT=7.77 min,purity=96%; Factor XIa Ki=0.19 nM, Plasma Kallikrein Ki=22 nM.

Example 192 Preparation of(9R,13S)-13-[4-(3-chloro-2,6-difluorophenyl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

192A. Preparation of 6-(3-chloro-2,6-difluorophenyl)pyrimidin-4-ol

6-(3-Chloro-2,6-difluorophenyl)pyrimidin-4-ol hydrobromide, prepared asdescribed in Intermediate 4, was partitioned between EtOAc and satNaHCO₃. The layers were separated and the organic layer was washed withbrine, dried over Na₂SO₄, filtered and concentrated to give a whitesolid. The solid was suspended in Et₂O and sonicated. The solid wascollected by filtration, rinsed with Et₂O, and dried under vacuum togive 6-(3-chloro-2,6-difluorophenyl)pyrimidin-4-ol as a white solid.MS(ESI) m/z: 243.0 (M+H)⁺ and 245.0 (M+2+H)⁺.

192B. Preparation of(9R,13S)-13-[4-(3-chloro-2,6-difluorophenyl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

(9R,13S)-13-[4-(3-Chloro-2,6-difluorophenyl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate (0.0092 g, 30%) was prepared in a similar manner as theprocedures described in Example 56, by using6-(3-chloro-2,6-difluorophenyl)pyrimidin-4-ol (10.8 mg, 0.045 mmol) and(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(0.015 g, 0.045 mmol), prepared as described in Intermediate 30. MS(ESI)m/z: 561.1 (M+H)⁺ and 563.1 (M+2+H)⁺. ¹H NMR (500 MHz, CD₃OD) δ 9.09 (s,1H), 8.77 (d, J=5.0 Hz, 1H), 7.79-7.72 (m, 2.25H), 7.67-7.60 (m, 1.5H),7.56-7.52 (m, 1.25H), 7.14 (dt, J=9.1, 1.9 Hz, 1H), 6.67 (s, 1H),6.11-6.04 (m, 1H), 2.76-2.69 (m, 1H), 2.42-2.33 (m, 1H), 2.13-2.02 (m,2H), 1.66-1.56 (m, 1H), 1.56-1.46 (m, 1H), 1.01 (d, J=6.9 Hz, 3H),0.73-0.60 (m, 1H). ¹⁹F NMR (471 MHz, CD₃OD) δ −114.75 (d, J=4.3 Hz),−115.47 (d, J=4.3 Hz), −77.66 (s). Analytical HPLC (Method A): RT=8.38min, purity=99.7%; Factor XIa Ki=30 nM, Plasma Kallikrein Ki=670 nM.

Example 193 Preparation of(9R,13S)-13-[4-(5-chloro-2-phenylphenyl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

(9R,13S)-13-[4-(5-Chloro-2-phenylphenyl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate (5 mg, 21% yield) was prepared in a similar manner asthe procedure described in Example 161, by replacing pyridin-3-ylboronicacid (4.76 mg, 0.039 mmol) with phenylboronic acid (4.72 mg, 0.039mmol). MS(ESI) m/z: 565.4 (M+H)⁺. ¹H NMR (500 MHz, CD₃OD) δ 8.92 (s,1H), 8.72 (d, J=5.0 Hz, 1H), 7.71 (d, J=2.2 Hz, 1H), 7.66 (s, 1H),7.55-7.50 (m, 2H), 7.48 (s, 1H), 7.41 (d, J=8.3 Hz, 1H), 7.34-7.26 (m,3H), 7.24-7.20 (m, 2H), 6.08 (d, J=0.8 Hz, 1H), 5.94 (dd, J=12.5, 4.0Hz, 1H), 4.04 (s, 3H), 2.73-2.65 (m, 1H), 2.34-2.24 (m, 1H), 2.10-1.94(m, 2H), 1.63-1.54 (m, 1H), 1.52-1.41 (m, 1H), 1.00 (d, J=6.9 Hz, 3H),0.74-0.59 (m, 1H). Analytical HPLC (Method A): RT=12.43 min, 98.2%purity; Factor XIa Ki=160 nM, Plasma Kallikrein Ki=4,700 nM.

Example 194 Preparation of(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-3,4,7,16-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

(9R,13S)-13-(4-{5-Chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-3,4,7,16-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate (5 mg, 4.9%) was prepared in a similar manner asExample 56 using6-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}pyrimidin-4-ol,prepared as described in Intermediate 15, and

(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,16-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one,prepared as described in Intermediate 43. MS(ESI) m/z: 660.2 (M+H)⁺. ¹HNMR (400 MHz, methanol-d4) δ 8.84 (d, J=0.7 Hz, 1H), 8.78 (s, 1H), 8.65(d, J=2.0 Hz, 1H), 8.34 (s, 1H), 8.27 (t, J=1.9 Hz, 1H), 7.92 (d, J=2.2Hz, 1H), 7.82-7.77 (m, 2H), 7.73-7.70 (m, 1H), 6.50 (d, J=0.7 Hz, 1H),5.79 (dd, J=12.9, 3.4 Hz, 1H), 2.58-2.48 (m, 2H), 2.22-2.14 (m, 1H),1.92-1.87 (m, 1H), 1.64-1.57 (m, 2H), 1.17 (d, J=6.8 Hz, 3H), 1.12-1.03(m, 1H). Analytical HPLC (Method A): RT=8.10 min, purity=90%; Factor XIaKi=0.13 nM, Plasma Kallikrein Ki=66 nM.

Example 195 Preparation of(9R,13S)-13-[4-(5-chloro-1-ethyl-1H-indazol-7-yl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

195A. Preparation of 6-(5-chloro-1-methyl-1H-indazol-7-yl)pyrimidin-4-ol

6-(5-Chloro-1-methyl-1H-indazol-7-yl)pyrimidin-4-ol was prepared in asimilar manner as Intermediate 22 replacing MeI with EtI. MS(ESI) m/z:275.1 (M+H)⁺ and 277.1 (M+2+H)⁺.

195B. Preparation of(9R,13S)-13-[4-(5-chloro-1-ethyl-1H-indazol-7-yl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate

(9R,13S)-13-[4-(5-Chloro-1-ethyl-1H-indazol-7-yl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one,trifluoroacetate (10.8 mg, 25%) was prepared in a similar manner asExample 56 using 6-(5-chloro-1-methyl-1H-indazol-7-yl)pyrimidin-4-ol and(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one,prepared as described in Intermediate 30. MS(ESI) m/z: 593.2 (M+H)⁺. ¹HNMR (400 MHz, CD₃OD) δ 9.12 (s, 1H), 8.76 (d, J=5.1 Hz, 1H), 8.10 (s,1H), 7.89 (d, J=2.0 Hz, 1H), 7.83-7.73 (m, 2H), 7.69-7.50 (m, 2H),7.45-7.41 (m, 1H), 6.73 (s, 1H), 6.12 (dd, J=12.9, 4.3 Hz, 1H),4.39-4.26 (m, 2H), 2.77-2.72 (m, 1H), 2.44-2.35 (m, 1H), 2.14-2.05 (m,2H), 1.65-1.50 (m, 2H), 1.23 (t, J=7.2 Hz, 3H), 1.01 (d, J=7.0 Hz, 2H),0.67 (br. s., 1H). Analytical HPLC (Method A): RT=8.69 min, purity=>99%;Factor XIa Ki=110 nM, Plasma Kallikrein Ki=8,400 nM.

Example 196 Preparation of(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

196A. Preparation of(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-9-methyl-3-{[2-(trimethylsilyl)ethoxy]methyl}-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

(9R,13S)-13-(4-{5-Chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-9-methyl-3-{[2-(trimethylsilyl)ethoxy]methyl}-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(760 mg, 0.975 mmol, 74% yield) was prepared in a similar manner as theprocedures described in Example 56, by using6-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol (0.452 g, 1.323 mmol), prepared as described inIntermediate 15, and

(9R,13S)-9-methyl-3-{[2-(trimethylsilyl)ethoxy]methyl}-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(0.550 g, 1.323 mmol), prepared as described in Intermediate 19. MS(ESI)m/z: 740.6 [M+H]⁺.

196B. Preparation of(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate

To a solution of(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-9-methyl-3-{[2-(trimethylsilyl)ethoxy]methyl}-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(760 mg, 1.027 mmol), in DCM (4.0 mL) was added TFA (1.0 mL, 12.98 mmol)and the resulting solution was stirred at rt for 30 min. The reactionmixture was then concentrated and the residue was purified by prep HPLCpurification to give(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate (480 mg, 92% yield). ¹H NMR (500 MHz, DMSO-d₆) δ 9.26(s, 1H), 9.21 (s, 1H), 8.63 (br. s., 1H), 8.49 (br. s., 1H), 7.96 (d,J=1.5 Hz, 1H), 7.87-7.78 (m, 2H), 7.47 (br. s., 1H), 7.24-6.98 (m, 1H),6.48 (s, 1H), 5.97 (br. s., 1H), 3.45-3.36 (m, 2H), 2.72 (br. s., 1H),2.32-2.15 (m, 2H), 1.80 (br. s., 1H), 1.52 (br. s., 1H), 1.38 (br. s.,1H), 0.92 (d, J=6.7 Hz, 3H), 0.59 (br. s., 1H). MS(ESI) m/z: 610.1[M+H]⁺. Analytical HPLC (Method B): RT=1.57 min, purity=97.0%; FactorXIa Ki=1.9 nM, Plasma Kallikrein Ki=205 nM.

Example 197 Preparation of(9R,13S)-13-{4-[3-chloro-2-fluoro-6-(1H-1,2,3,4-tetrazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate

(9R,13S)-13-{4-[3-Chloro-2-fluoro-6-(1H-1,2,3,4-tetrazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate (6.9 mg, 16% yield) was prepared in a similar manner asthe procedure described in Example 196 by using(9R,13S)-13-amino-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one,prepared as described in Intermediate 32. MS(ESI) m/z: 575.2 (M+H)⁺. ¹HNMR (400 MHz, CD₃OD) δ 9.46 (br. s., 1H), 8.76 (d, J=8.1 Hz, 2H), 7.91(d, J=6.8 Hz, 1H), 7.80 (br. s., 1H), 7.62 (d, J=7.0 Hz, 2H), 7.53 (br.s., 1H), 6.70 (br. s., 1H), 5.95 (br. s., 1H), 4.09 (br. s., 3H), 2.71(br. s., 1H), 2.32 (br. s., 1H), 2.05 (br. s., 2H), 1.62 (br. s., 1H),1.46 (br. s., 1H), 1.03 (br. s., 3H), 0.77 (br. s., 1H) Analytical HPLC(Method A): RT=6.71 min, purity=>99%; Factor XIa Ki=0.1 nM, PlasmaKallikrein Ki=8 nM.

Example 198 Preparation of(9R,13S)-13-{4-[3-chloro-2-fluoro-6-(1H-1,2,3,4-tetrazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate

(9R,13S)-13-{4-[3-Chloro-2-fluoro-6-(1H-1,2,3,4-tetrazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate (9.7 mg, 33% yield) was prepared in a similar manner asthe procedure described in Example 196 by using(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one,prepared as described in Intermediate 35. MS(ESI) m/z: 610.3 (M+H)⁺. ¹HNMR (400 MHz, CD₃OD) δ 9.42 (s, 1H), 8.17 (s, 1H), 7.89 (dd, J=8.7, 7.6Hz, 1H), 7.81-7.75 (m, 2H), 7.65-7.46 (m, 4H), 7.38 (d, J=7.7 Hz, 1H),6.71 (d, J=0.9 Hz, 1H), 5.81 (dd, J=12.9, 3.4 Hz, 1H), 2.56-2.44 (m,1H), 2.40-2.25 (m, 1H), 2.17-2.05 (m, 1H), 1.94-1.82 (m, 1H), 1.63-1.47(m, 2H), 1.27-1.17 (m, 1H), 1.15 (d, J=6.8 Hz, 3H). Analytical HPLC(Method A): RT=8.62 min, purity=>99%; Factor XIa Ki=0.1 nM, PlasmaKallikrein Ki=4 nM.

Example 199 Preparation of(9R,13S)-13-{4-[5-chloro-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

199A. Preparation of6-(5-chloro-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl)pyrimidin-4-ol

6-(5-Chloro-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl)pyrimidin-4-ol (25mg, 62%) was prepared in a similar manner as Intermediate 22 replacingMeI with 2-bromo-1,1,1-trifluoroethane. MS(ESI) m/z: 329 (M+H)⁺ and 331(M+2+H)⁺.

199B. Preparation of(9R,13S)-13-{4-[5-chloro-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate

(9R,13S)-13-{4-[5-Chloro-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate (14.5 mg, 25%) was prepared in a similar manner asExample 56 using6-(5-chloro-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl)pyrimidin-4-ol and(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one,prepared as described in Intermediate 30. MS(ESI) m/z: 647.2 (M+H)⁺ and649.2 (M+2+H)⁺. ¹H NMR (400 MHz, CD₃OD) δ 9.17 (s, 1H), 8.74 (d, J=5.1Hz, 1H), 8.27-8.19 (m, 1H), 7.97 (d, J=2.0 Hz, 1H), 7.84-7.72 (m, 2H),7.68-7.57 (m, 2H), 7.56-7.51 (m, 1H), 6.77 (s, 1H), 6.14 (dd, J=12.9,4.3 Hz, 1H), 5.51-5.37 (m, 2H), 2.77-2.70 (m, 1H), 2.45-2.35 (m, 1H),2.08 (t, J=12.4 Hz, 2H), 1.64-1.51 (m, 2H), 1.00 (d, J=6.8 Hz, 3H), 0.68(br. s., 1H). Analytical HPLC (Method A): RT=9.21 min, purity=>99%;Factor XIa Ki=57 nM, Plasma Kallikrein Ki=1,500 nM.

Example 200 Preparation of(9R,13S)-13-{4-[5-chloro-2-(1H-1,2,3,4-tetrazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate

(9R,13S)-13-{4-[5-Chloro-2-(1H-1,2,3,4-tetrazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate (22.1 mg, 44% yield) was prepared in a similar manneras the procedure described in Example 198 by replacing6-[3-chloro-2-fluoro-6-(1H-1,2,3,4-tetrazol-1-yl)phenyl]pyrimidin-4-olwith 6-[5-chloro-2-(1H-1,2,3,4-tetrazol-1-yl)phenyl]pyrimidin-4-ol,prepare as described in Intermediate 20. MS(ESI) m/z: 593.2 (M+H)⁺. ¹HNMR (400 MHz, CD₃OD) δ 9.38 (s, 1H), 8.73-8.65 (m, 2H), 7.84 (d, J=2.2Hz, 1H), 7.79-7.42 (m, 6H), 6.46 (s, 1H), 5.88 (dd, J=12.5, 4.2 Hz, 1H),2.71-2.58 (m, 1H), 2.32-2.19 (m, 1H), 2.04-1.89 (m, 2H), 1.60-1.47 (m,1H), 1.45-1.30 (m, 1H), 0.94 (d, J=6.8 Hz, 3H), 0.60 (br. s., 1H).Analytical HPLC (Method A): RT=7.93 min, purity=>99%; Factor XIa Ki=0.1nM, Plasma Kallikrein Ki=10 nM.

Example 201 Preparation of(9R,13S)-13-{4-[5-chloro-2-(1H-1,2,3,4-tetrazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

(9R,13S)-13-{4-[5-Chloro-2-(1H-1,2,3,4-tetrazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(10.5 mg, 40% yield) was prepared in a similar manner as the proceduredescribed in Example 200 by replacing(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onewith(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one,prepare as described in Intermediate 35. MS(ESI) m/z: 592.3 (M+H)⁺. ¹HNMR (400 MHz, CD₃OD) δ 9.39 (s, 1H), 8.09 (s, 1H), 7.86 (d, J=2.4 Hz,1H), 7.78-7.42 (m, 7H), 7.34 (d, J=7.5 Hz, 1H), 6.51 (s, 1H), 5.76 (dd,J=12.8, 3.1 Hz, 1H), 2.51-2.38 (m, 1H), 2.36-2.21 (m, 1H), 2.11-1.99 (m,1H), 1.90-1.77 (m, 1H), 1.58-1.41 (m, 2H), 1.21-1.03 (m, 4H) AnalyticalHPLC (Method A): RT=8.50 min, purity=>99%; Factor XIa Ki=0.1 nM, PlasmaKallikrein Ki=6 nM.

Example 202 Preparation of(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-5-fluoro-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

202A. Preparation of6-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-fluoropyrimidin-4-ol

To a solution of6-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol (100mg, 0.325 mmol) in CH₃CN (2 mL) was added SELECTFLUOR® (115 mg, 0.325mmol). The mixture was stirred at rt for 1.5 h then DMF (0.5 ml) wasadded to solubilize the mixture. The reaction was heated at 85° C.overnight. The reaction mixture was purified using reverse phasechromatography. After the pure fractions were concentrated, the residuewas partitioned between EtOAc and sat NaHCO₃ and the layers wereseparated. The aqueous layer was extracted with EtOAc (2×). The combinedorganic layers were dried with MgSO₄, filtered, and concentrated to give6-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-fluoropyrimidin-4-ol(13 mg, 12.3% yield) as an off-white foam. MS(ESI) m/z: 326.1 (M+H)⁺. ¹HNMR (400 MHz, CDCl₃) δ 7.94 (s, 1H), 7.79 (s, 1H), 7.76 (d, J=2.2 Hz,1H), 7.66 (dd, J=8.5, 2.3 Hz, 1H), 7.49 (d, J=8.6 Hz, 1H).

202B. Preparation of(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-5-fluoro-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate

(9R,13S)-13-{4-[5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-5-fluoro-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate (3 mg, 10% yield) was prepared in a similar manner asthe procedure described in Example 56, using6-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-fluoropyrimidin-4-ol.MS(ESI) m/z: 608.1 (M+H)⁺. ¹H NMR (400 MHz, CD₃₀OD) δ 8.78-8.68 (m, 1H),8.41 (s, 1H), 7.86 (d, J=2.4 Hz, 1H), 7.81-7.74 (m, 1H), 7.71 (d, J=8.6Hz, 2H), 7.52 (dd, J=5.1, 1.5 Hz, 1H), 7.49 (s, 1H), 6.00 (dd, J=12.4,3.9 Hz, 1H), 4.05 (s, 3H), 2.70 (m, 1H), 2.36-2.23 (m, 1H), 2.14-1.96(m, 2H), 1.67-1.54 (m, 1H), 1.53-1.41 (m, 1H), 1.01 (d, J=7.0 Hz, 3H),0.68 (m., 1H). ¹⁹F NMR (376 MHz, CD₃₀OD) δ −77.46 (s), −147.07 (s).Analytical HPLC (Method A): RT=9.43 min, purity=93%; Factor XIa Ki=0.12nM, Plasma Kallikrein Ki=13 nM.

Example 203 Preparation of(9R,13S)-13-{5-bromo-4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

203A. Preparation of6-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-fluoropyrimidin-4-ol

To a solution of6-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol (100mg, 0.325 mmol) in CH₃CN (2 mL) was added NBS (63.5 mg, 0.357 mmol). Themixture was stirred at rt for 1.5 h. The reaction was partitionedbetween DCM and water and the layers were separated. The aqueous layerwas extracted with DCM (2×). The combined organic layers wasconcentrated and then purified on normal phase chromatography to give5-bromo-6-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol (117 mg, 93% yield) as white foam. MS(ESI) m/z: 388.0(M+H)⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.11 (s, 1H), 7.71 (s, 1H), 7.66-7.63(m, 1H), 7.63-7.62 (m, 1H), 7.53 (d, J=8.4 Hz, 1H).

203B. Preparation of(9R,13S)-13-{5-bromo-4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-39-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate

(9R,13S)-13-{5-Bromo-4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate (4 mg, 13% yield) was prepared in a similar manner asthe procedure described in Example 56, by using5-bromo-6-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol,prepared as described in Example 203A. MS(ESI) m/z: 670.0 (M+H)⁺. ¹H NMR(400 MHz, CD₃OD) δ 8.87 (s, 1H), 8.73 (d, J=5.1 Hz, 1H), 8.35 (s, 1H),7.80-7.64 (m, 4H), 7.57-7.45 (m, 2H), 5.99 (dd, J=12.8, 3.7 Hz, 1H),4.05 (s, 3H), 2.72 (m, 1H), 2.40-2.22 (m, 1H), 2.14-2.00 (m, 2H),1.69-1.55 (m, 1H), 1.49 (t, J=10.0 Hz, 1H), 1.01 (d, J=6.8 Hz, 3H), 0.69(m, 1H). Analytical HPLC (Method A): RT=11.12 min, purity=99%; FactorXIa Ki=4.6 nM, Plasma Kallikrein Ki=220 nM.

Example 204 Preparation of(9R,13S)-13-(4-{5-chloro-3-fluoro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

204A. Preparation of6-(5-chloro-3-fluoro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol

6-(5-Chloro-3-fluoro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol was prepared in a similar manner as Intermediate 15,starting from 2-bromo-4-chloro-6-fluoroaniline instead of2-bromo-4-chloroaniline. MS(ESI) m/z: 360.0 (M+H)⁺.

204B. Preparation of(9R,13S)-13-(4-{5-chloro-3-fluoro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate

(9R,13S)-13-(4-{5-Chloro-3-fluoro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate (25 mg, 23.4%) was prepared in a similar manner asExample 56 using6-(5-chloro-3-fluoro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-oland(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one,prepared as described in Intermediate 30. MS(ESI) m/z: 575.1 (M+H)⁺. ¹HNMR (400 MHz, CD₃OD) δ 8.83 (s, 1H), 8.70 (s, 1H), 8.60 (d, J=5.3 Hz,1H), 7.72-7.53 (m, 5H), 7.43-7.38 (m, 1H), 6.36 (d, J=0.7 Hz, 1H), 5.89(dd, J=12.7, 4.5 Hz, 1H), 2.60 (td, J=6.7, 3.0 Hz, 1H), 2.14 (tt,J=12.8, 4.2 Hz, 1H), 1.98-1.82 (m, 2H), 1.53-1.30 (m, 2H), 0.88 (d,J=7.0 Hz, 3H), 0.51 (br. s., 1H). Analytical HPLC (Method A): RT=9.04min, purity=99.5%; Factor XIa Ki=6.8 nM, Plasma Kallikrein Ki=2,700 nM.

Example 205 Preparation of(10R,14S)-14-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-10-methyl-5,8-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-9-one

(10R,14S)-14-(4-{5-Chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-10-methyl-5,8-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-9-onetrifluoroacetate (0.0076 g, 36%) was prepared according to theprocedures described in Example 46 by using6-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}pyrimidin-4-ol,prepared as described in Example 15B,(10R,14S)-14-amino-10-methyl-5,8-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-9-one,prepared as described in Intermediate 38, and 4-bromopyridin-3-amine inIntermediate 38B. MS(ESI) m/z: 620.1 (M+H)⁺. ¹H NMR (400 MHz, CD₃OD) δ8.81 (d, J=0.7 Hz, 1H), 8.77 (s, 2H), 8.29 (s, 1H), 8.08 (d, J=5.7 Hz,1H), 7.91-7.84 (m, 2H), 7.82-7.60 (m, 4H), 7.42-7.34 (m, 1H), 6.49 (d,J=0.4 Hz, 1H), 5.80 (dd, J=13.0, 3.5 Hz, 1H), 2.64-2.51 (m, 1H),2.39-2.26 (m, 1H), 2.18-2.06 (m, 1H), 1.99-1.88 (m, 1H), 1.63-1.30 (m,3H), 1.16 (d, J=6.8 Hz, 3H). Analytical HPLC (Method A): RT=6.87 min,purity=90%; Factor XIa Ki=0.11 nM, Plasma Kallikrein Ki=11 nM.

Example 206 Preparation of(10R,14S)-14-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-10-methyl-5,8-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-9-one

(10R,14S)-14-{4-[5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-10-methyl-5,8-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-9-onetrifluoroacetate (0.0062 g, 31%) was prepared according to theprocedures described in Example 205 by using6-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]pyrimidin-4-ol,prepared as described in Intermediate 9E. MS(ESI) m/z: 586.1 (M+H)⁺. ¹HNMR (400 MHz, CD₃OD) δ 8.70 (d, J=5.3 Hz, 1H), 8.64 (s, 1H), 8.37-8.28(m, 2H), 7.93-7.84 (m, 3H), 7.75 (dd, J=8.6, 2.2 Hz, 1H), 7.68-7.61 (m,3H), 7.43-7.35 (m, 1H), 6.42 (s, 1H), 5.82 (dd, J=13.0, 3.5 Hz, 1H),2.63-2.52 (m, 1H), 2.41-2.28 (m, 1H), 2.20-2.08 (m, 1H), 1.98-1.87 (m,1H), 1.65-1.45 (m, 2H), 1.41-1.29 (m, 1H), 1.17 (d, J=7.0 Hz, 3H).Analytical HPLC (Method A): RT=6.26 min, purity=90%; Factor XIa Ki=0.2nM, Plasma Kallikrein Ki=17 nM.

Example 207 Preparation of(9R,13S)-13-[4-(6-chloro-1H-1,3-benzodiazol-4-yl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

207A. Preparation of6-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazole

4-Bromo-6-chloro-1H-benzo[d]imidazole (0.600 g, 2.59 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (0.790 g,3.11 mmol), KOAc (0.763 g, 7.78 mmol) were added to dioxane (10.9 mL).After bubbling Ar through the solution for 2 min, Pd(dppf)Cl₂CH₂Cl₂complex (0.106 g, 0.130 mmol) was added and the mixture heated at 110°C. overnight. The reaction mixture was cooled to rt and partitionedbetween EtOAc and water. The organic phase separated and washed with satNaHCO₃ and brine, dried over MgSO₄, filtered, concentrated to yield acrude dark solid product which was carried forward to the next reaction.MS(ESI) m/z: 197.0 (M-C₆H₁₀+H)⁺.

207B. Preparation of6-chloro-4-(6-methoxypyrimidin-4-yl)-1H-benzo[d]imidazole

4-Chloro-6-methoxypyrimidine (0.562 g, 3.89 mmol),6-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazole(0.722 g, 2.59 mmol) and 2 M aq Na₂CO₃ (0.549 g, 5.18 mmol) in DME(20.74 mL), EtOH (2.59 mL) was purged with Ar for several min. ThenPdCl₂(dppf)-CH₂Cl₂ Adduct (0.212 g, 0.259 mmol) was added and heated to90° C. After 2 h, the reaction was cooled to rt, diluted with water andextracted with EtOAc. The organic layer washed with brine, dried overNa₂SO₄, filtered, and concentrated to give a brown oil. The crudematerial was purified by normal phase chromatography using EtOAc andMeOH as eluants to give6-chloro-4-(6-methoxypyrimidin-4-yl)-1H-benzo[d]imidazole (148 mg, 22%).MS(ESI) m/z: 261.1 (M+H)⁺ and 263.1 (M+2+H)⁺. ¹H NMR (500 MHz, DMSO-d₆)δ 8.93 (d, J=1.1 Hz, 1H), 8.42 (s, 1H), 8.36 (br. s., 1H), 8.20 (d,J=1.9 Hz, 1H), 7.84 (s, 1H), 4.02 (s, 3H).

207C. Preparation of 6-(6-chloro-1H-benzo[d]imidazol-4-yl)pyrimidin-4-ol

To a clear solution of6-chloro-4-(6-methoxypyrimidin-4-yl)-1H-benzo[d]imidazole (0.148 g,0.568 mmol) in AcOH (2.88 ml) was added 63% aq HBr (0.548 ml, 4.54 mmol)and the reaction mixture was heated to 80° C. After 1 h, the solutionwas cooled to rt, diluted with EtOAc (10 ml), then quenched with sat aqNaHCO₃ (20 ml). The aqueous layer was extracted with EtOAc (3×10 ml).The combined organic layer washed with brine (10 ml), dried over Na₂SO₄,filtered and concentrated. The crude product was triturated with pet.ether, filtered, and dried under vacuum to give6-(6-chloro-1H-benzo[d]imidazol-4-yl)pyrimidin-4-ol as a beige colorsolid. MS(ESI) m/z: 247 (M+H)⁺ and 249 (M+2+H)⁺. ¹H NMR (400 MHz,DMSO-d₆) δ 8.39 (s, 1H), 8.35-8.28 (m, 1H), 8.03 (d, J=2.0 Hz, 1H), 7.78(d, J=2.2 Hz, 2H).

207D. Preparation of(9R,13S)-13-[4-(6-chloro-1H-1,3-benzodiazol-4-yl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate

(9R,13S)-13-[4-(6-Chloro-1H-1,3-benzodiazol-4-yl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate (0.7 mg, 0.77%) was prepared in a similar manner asExample 56 using 6-(6-chloro-1H-benzo[d]imidazol-4-yl)pyrimidin-4-ol and(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one,prepared as described in Intermediate 30. MS(ESI) m/z: 565 (M+H)⁺. ¹HNMR (500 MHz, DMSO-d₆) δ 9.43 (s, 1H), 9.07 (br. s., 1H), 8.76 (d, J=4.6Hz, 1H), 8.43 (br. s., 1H), 8.10 (d, J=17.7 Hz, 1H), 7.99-7.90 (m, 2H),7.82-7.73 (m, 2H), 7.44 (d, J=4.6 Hz, 1H), 5.99 (d, J=11.0 Hz, 1H), 2.09(d, J=8.9 Hz, 1H), 1.98 (br. s., 1H), 1.55 (br. s., 4H), 1.40 (br. s.,1H), 0.90 (d, J=6.7 Hz, 3H). Analytical HPLC (Method C): RT=1.20 min,purity=100%; Factor XIa Ki=120 nM.

Example 208 Preparation of methyl4-[(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2,5,14,16-pentaen-4-yl]piperidine-1-carboxylate

(9R,13S)-13-{4-[5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-4-(piperidin-4-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2,5,14,16-pentaen-8-one,prepared as described in Example 328 (0.015 g, 0.023 mmol), methylchloroformate (2.2 mg, 0.023 mmol), and Et₃N (0.016 mL, 0.114 mmol) weredissolved in THF (1 mL) and stirred at rt for 3 h, then concentrated.The residue was purified by reverse phase chromatography to give methyl4-[(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2,5,14,16-pentaen-4-yl]piperidine-1-carboxylate(10 mg, 61%) as a white solid. MS(ESI) m/z: 717.2 (M+H)⁺. ¹H NMR (400MHz, CD₃OD) δ 8.69-8.64 (m, 1H), 8.63-8.57 (m, 1H), 8.36 (s, 1H), 7.91(d, J=2.4 Hz, 2H), 7.83 (s, 1H), 7.79-7.72 (m, 1H), 7.68 (s, 1H),7.67-7.65 (m, 1H), 7.65-7.61 (m, 1H), 6.40 (d, J=0.4 Hz, 1H), 6.11-5.99(m, 1H), 4.52-4.41 (m, 1H), 4.34-4.22 (m, 2H), 3.74 (s, 3H), 3.17-2.97(m, 2H), 2.86-2.75 (m, 1H), 2.36-2.13 (m, 4H), 2.13-1.97 (m, 3H),1.81-1.63 (m, 1H), 1.61-1.48 (m, 1H), 1.09 (d, J=7.0 Hz, 3H). AnalyticalHPLC (Method A): RT=7.40 min, purity=99%; Factor XIa Ki=7 nM, PlasmaKallikrein Ki=460 nM.

Example 209 Preparation of(9R,13S)-13-(4-{4-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

(9R,13S)-13-(4-{4-Chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one (4 mg, 20% yield), was prepared as asolid via the coupling of6-{4-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}pyrimidin-4-ol(0.01 g, 0.028 mmol) and(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one (0.01 g, 0.028 mmol) using the HATU, DBU couplingmethodology as described in Example 56. LCMS m/z=660.2 (M+H). ¹H NMR(400 MHz, CD₃OD) δ 8.87-8.80 (m, 2H), 8.76-8.71 (m, 1H), 7.86-7.83 (m,2H), 7.82-7.80 (m, 1H), 7.77-7.76 (m, 1H), 7.72-7.66 (m, 2H), 7.55-7.52(m, 1H), 6.49-6.46 (s, 1H), 6.08-5.99 (m, 1H), 2.78-2.68 (m, 1H),2.36-2.21 (m, 1H), 2.12-1.99 (m, 3H), 1.69-1.41 (m, 4H), 1.05-0.96 (d,3H), 0.74-0.54 (m, 1H). Analytical HPLC (Method A) RT=8.77 min,purity=95%; Factor XIa Ki=48 nM.

Example 210 Preparation of(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-5-methyl-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

210A. Preparation of4-chloro-2-(6-methoxy-5-methylpyrimidin-4-yl)aniline

4-Chloro-2-(6-methoxy-5-methylpyrimidin-4-yl)aniline (230 mg, 73% yield)was prepared in a similar manner as the procedure described inIntermediate 9B, by replacing 4-chloro-6-methoxypyrimidine with4-chloro-6-methoxy-5-methylpyrimidine (200 mg, 1.261 mmol). MS(ESI) m/z:250.1 (M+H)⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.68 (s, 1H), 7.15 (dd, J=8.6,2.6 Hz, 1H), 7.09 (d, J=2.6 Hz, 1H), 6.72 (d, J=8.6 Hz, 1H), 4.25 (br.s., 2H), 4.06 (s, 3H), 2.14 (s, 3H), 1.33-1.20 (m, 12H).

210B. Preparation of4-(5-chloro-2-(4-(trimethylsilyl)-1H-1,2,3-triazol-1-yl)phenyl)-6-methoxy-5-methylpyrimidine

4-(5-Chloro-2-(4-(trimethylsilyl)-1H-1,2,3-triazol-1-yl)phenyl)-6-methoxy-5-methylpyrimidine(70 mg, 20% yield) was prepared in a similar manner as the proceduredescribed in Intermediate 9C, by replacing4-chloro-2-(6-methoxypyrimidin-4-yl)aniline with4-chloro-2-(6-methoxy-5-methylpyrimidin-4-yl)aniline (230 mg, 0.921mmol). MS(ESI) m/z: 374.4 (M+H)⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.36 (s,1H), 7.44-7.29 (m, 2H), 7.25 (d, J=2.2 Hz, 1H), 7.12 (s, 1H), 3.76-3.70(m, 3H), 0.04-0.05 (m, 9H).

210C. Preparation of4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-6-methoxy-5-methylpyrimidine

4-(5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-6-methoxy-5-methylpyrimidine(29 mg, 46% yield) was prepared in a similar manner as the proceduredescribed in Intermediate 9D, by replacing4-{5-chloro-2-[4-(trimethylsilyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-methoxypyrimidinewith4-(5-chloro-2-(4-(trimethylsilyl)-1H-1,2,3-triazol-1-yl)phenyl)-6-methoxy-5-methylpyrimidine(70 mg, 0.187 mmol). MS(ESI) m/z: 336.4 (M+H)⁺. ¹H NMR (400 MHz, CDCl₃)δ 8.60 (s, 1H), 7.61-7.58 (m, 2H), 7.50 (s, 1H), 7.47 (d, J=2.0 Hz, 1H),4.02 (s, 3H), 1.83 (s, 3H).

210D. Preparation of6-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-methylpyrimidin-4-ol

6-(5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-methylpyrimidin-4-ol(10 mg, 36% yield) was prepared in a similar manner as the proceduredescribed in Intermediate 9E, by replacing4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-methoxypyrimidinewith4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-6-methoxy-5-methylpyrimidine(29 mg, 0.086 mmol). MS(ESI) m/z: 322.0 (M+H)⁺. ¹H NMR (400 MHz, CD₃OD)δ 8.25 (s, 1H), 7.98 (s, 1H), 7.72 (d, J=2.0 Hz, 1H), 7.71 (d, J=0.4 Hz,1H), 7.66 (dd, J=2.1, 0.6 Hz, 1H), 1.79 (s, 3H).

210E. Preparation of(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-5-methyl-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate

(9R,13S)-13-{4-[5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-5-methyl-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate (8.8 mg, 37% yield) was prepared in a similar manner asthe procedure described in Example 56, by using6-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-methylpyrimidin-4-ol(0.010 g, 0.031 mmol). MS(ESI) m/z: 604.1 (M+H)⁺. ¹H NMR (400 MHz,CD₃OD) δ 8.79-8.70 (m, 2H), 8.27 (s, 1H), 7.78 (s, 1H), 7.77-7.69 (m,2H), 7.68 (d, J=2.0 Hz, 1H), 7.60 (dd, J=5.3, 1.5 Hz, 1H), 7.50 (s, 1H),5.95 (dd, J=12.5, 4.2 Hz, 1H), 4.06 (s, 3H), 2.70 (m, 1H), 2.40-2.29 (m,1H), 2.13-1.99 (m, 2H), 1.77 (s, 3H), 1.67-1.55 (m, 1H), 1.47 (m, 1H),1.02 (d, J=6.8 Hz, 3H), 0.77 (m., 1H); Analytical HPLC (Method A):RT=7.79 min, purity=93%; Factor XIa Ki=3.5 nM, Plasma Kallikrein Ki=240nM.

Example 211 Preparation of(9R,13S)-13-[4-(5-chloro-2-iodophenyl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

211A. Preparation of 4-(5-chloro-2-iodophenyl)-6-methoxypyrimidine

The solution of 4-chloro-2-(6-methoxypyrimidin-4-yl)aniline (2 g, 8.49mmol), prepared as described in Intermediate 8A, in ACN (56.6 ml) wascooled to 0° C., then p-TsOH.H₂O (4.04 g, 21.22 mmol) was added. Asolution of NaNO₂ (1.171 g, 16.97 mmol) and NaI (3.18 g, 21.22 mmol) inwater (28.3 ml) was added slowly and the reaction turned into a darkbrown solution. After a few min, the reaction turned cloudy. Thereaction was stirred at 0° C. for 1 h, then the reaction was warmed tort. After 18 h, the reaction was quenched with sat NaHCO₃ and extractedwith EtOAc. The organic layer was washed with sat aq Na₂S₂O₃, brine,dried over Na₂SO₄, filtered, and concentrated to yield a solid.Purification by normal phase chromatography afforded4-(5-chloro-2-iodophenyl)-6-methoxypyrimidine (2.13 g, 72% yield) as awhite solid. MS(ESI) m/z: 347.2 (M+H)⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.87(d, J=1.1 Hz, 1H), 7.88 (d, J=8.3 Hz, 1H), 7.44 (d, J=2.8 Hz, 1H), 7.11(dd, J=8.5, 2.8 Hz, 1H), 6.93 (d, J=1.4 Hz, 1H), 4.06 (s, 3H).

211B. Preparation of 6-(5-chloro-2-iodophenyl)pyrimidin-4-ol

6-(5-Chloro-2-iodophenyl)pyrimidin-4-ol (0.24 g, 100% yield) wasprepared in a similar manner as the procedure described in Example 140B,by replacing4-(5-chloro-2-(1-(difluoromethyl)-1H-pyrazol-4-yl)phenyl)-6-methoxypyrimidinewith 4-(5-chloro-2-iodophenyl)-6-methoxypyrimidine (0.25 g, 0.721 mmol),and the reaction time was 1 h at 85° C. MS(ESI) m/z: 333.0 (M+H)⁺. ¹HNMR (400 MHz, CD₃OD) δ 8.27 (d, J=0.9 Hz, 1H), 7.95 (d, J=8.6 Hz, 1H),7.47 (d, J=2.6 Hz, 1H), 7.21 (dd, J=8.6, 2.6 Hz, 1H), 6.54 (d, J=0.9 Hz,1H).

211C. Preparation of(9R,13S)-13-[4-(5-chloro-2-iodophenyl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate

(9R,13S)-13-[4-(5-Chloro-2-iodophenyl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate (125 mg, 68% yield) was prepared in a similar manner asthe procedure described in Example 56, by using6-(5-chloro-2-iodophenyl)pyrimidin-4-ol (100 mg, 0.301 mmol). MS(ESI)m/z: 615.4 (M+H)⁺. ¹H NMR (400 MHz, CD₃OD) δ 9.05 (s, 1H), 8.75 (d,J=5.3 Hz, 1H), 7.95 (d, J=8.4 Hz, 1H), 7.74 (s, 1H), 7.54 (dd, J=5.1,1.5 Hz, 1H), 7.51-7.49 (m, 2H), 7.21 (dd, J=8.5, 2.5 Hz, 1H), 6.60 (s,1H), 6.07 (dd, J=12.8, 4.4 Hz, 1H), 4.05 (s, 3H), 2.77-2.68 (m, 1H),2.38 (tt, J=12.7, 4.3 Hz, 1H), 2.16-2.02 (m, 2H), 1.68-1.44 (m, 2H),1.02 (d, J=6.8 Hz, 3H), 0.79-0.64 (m, 1H). Analytical HPLC (Method A):RT=8.71 min, 99.6% purity; Factor XIa Ki=12 nM, Plasma KallikreinK_(i)=140 nM.

Example 212 Preparation of(9R,13S)-13-{4-[3-chloro-2-fluoro-6-(4-phenyl-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate

(9R,13S)-13-{4-[3-Chloro-2-fluoro-6-(4-phenyl-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(3 mg, 19% yield) was prepared in a similar manner as the proceduredescribed in Example 56, by using6-[3-chloro-2-fluoro-6-(4-phenyl-1H-1,2,3-triazol-1-yl)phenyl]pyrimidin-4-ol(9 mg, 0.024 mmol), prepared as described in Intermediate 9, and(9R,13S)-13-amino-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(7.3 mg, 0.024 mmol). LCMS m/z 650.3 (M+H). ¹H NMR (400 MHz, CD₃OD) δ8.81-8.77 (m, 1H), 8.62-8.57 (m, 1H), 8.56-8.54 (m, 1H), 7.93-7.87 (m,1H), 7.84-7.78 (m, 3H), 7.66-7.62 (dd, 1H), 7.61-7.57 (m, 1H), 7.52 (bs,1H), 7.49-7.44 (m, 2H), 7.43-7.38 (m, 1H), 6.68-6.64 (m, 1H), 5.98-5.94(m, 1H), 4.07 (s, 3H), 2.75-2.61 (m, 1H), 2.39-2.22 (m, 1H), 2.10-1.99(m, 2H), 1.65-1.53 (m, 1H), 1.49-1.33 (m, 1H), 1.07-1.00 (d, 3H),0.86-0.67 (m, 1H); Factor XIa Ki=0.81 nM, Plasma Kallikrein Ki=28 nM.

Example 213 Preparation ofN-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}-3-fluorophenyl)carbamatetrifluoroacetate

213A. Preparation ofN-[4-chloro-3-fluoro-2-(6-methoxypyrimidin-4-yl)phenyl]carbamate

4-Chloro-3-fluoro-2-(6-methoxypyrimidin-4-yl)aniline (0.024 g, 0.095mmol), was dissolved in DCM (5 ml). To this solution was addedsequentially TEA (1 mL) followed by methyl chloroformate (8.94 mg, 0.095mmol) and the solution was stirred at rt. After 2 h, the reaction wasconcentrated in vacuo to an oil and quenched with dilute HCl (5 mL). Theorganics were extracted with EtOAc (2×25 mL), dried with MgSO₄ andevaporated to an oil. LCMS m/z 312.1 (M+H). ¹H NMR (400 MHz, CDCl₃) δ10.30-10.24 (m, 1H), 8.84-8.81 (m, 1H), 8.00-7.92 (m, 1H), 7.40-7.32 (m,1H), 7.05-7.01 (m, 1H), 3.98 (s, 3H), 3.67 (s, 3H). The crude productwas taken in a small vial and dissolved in AcOH (1 mL) and to this wasadded 48% HBr (0.1 mL) and heated at 80° C. until reaction was complete.The reaction mixture was concentrated and quenched with water (25 mL),extracted with EtOAc (2×25 mL). The combined organic layers was driedand evaporated to giveN-[4-chloro-3-fluoro-2-(6-methoxypyrimidin-4-yl)phenyl]carbamate as awhite film (13 mg). LCMS m/z 299.1 (M+H).

213B. Preparation ofN-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}-3-fluorophenyl)carbamate

N-(4-Chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}-3-fluorophenyl)carbamate(1.1 mg, 4.21% yield) was prepared following the procedure described inExample 56 by usingN-[4-chloro-3-fluoro-2-(6-hydroxypyrimidin-4-yl)phenyl]carbamate (13 mg,0.044 mmol),(9R,13S)-13-amino-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(15 mg, 0.044 mmol). LCMS m/z 580.1 (M+H). ¹H NMR (500 MHz, DMSO-d₆) δ9.39-9.34 (m, 1H), 9.24-9.21 (m, 1H), 9.05-9.02 (m, 1H), 8.74-8.70 (m,1H), 7.74-7.57 (m, 3H), 7.49 (s, 1H), 6.61-6.55 (m, 1H), 5.99-5.87 (m,1H), 4.04-3.98 (m, 3H), 3.65-3.59 (m, 3H), 2.70-2.62 (m, 1H), 2.40-2.32(m, 1H), 2.18-2.09 (m, 1H), 1.96-1.85 (m, 1H), 1.53-1.30 (m, 2H),0.94-0.87 (m, 3H), 0.56-0.36 (m, 1H). Ortho RT. 1.605 min purity 97%;Factor XIa Ki=110 nM.

Example 214 Preparation of(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6])octadeca-1(18),2(6),4,14,16-pentaen-15-ium-15-olate

(9R,13S)-13-{4-[5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one,prepared as described in Example 88, was dissolved in EtOAc (2 mL) andm-CPBA (0.021 g, 0.120 mmol) was added at rt. After stirring overnight,the reaction was concentrated and purified by reverse phasechromatography to give(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-15-ium-15-olate(11 mg, 15%) as a white solid. MS(ESI) m/z: 642.2 (M+H)⁺. ¹H NMR (500MHz, DMSO-d₆) δ 9.54 (s, 1H), 8.71 (s, 1H), 8.40 (d, J=6.7 Hz, 2H),7.98-7.86 (m, 3H), 7.85-7.76 (m, 2H), 7.72 (d, J=8.5 Hz, 1H), 7.55 (d,J=5.2 Hz, 1H), 6.32 (s, 1H), 5.49-5.31 (m, 1H), 2.48-2.34 (m, 1H),2.03-1.92 (m, 1H), 1.82-1.70 (m, 1H), 1.48-1.36 (m, 1H), 1.06 (d, J=6.1Hz, 3H), 1.01-0.85 (m, 1H). Analytical HPLC (Method C): RT=1.45 min,purity=100%; Factor XIa Ki=0.35 nM, Plasma Kallikrein Ki=74 nM.

Example 215 Preparation of(9R,13S)-13-(4-{5-chloro-2-[4-(pyridin-3-yl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate

215A. Preparation of6-{5-chloro-2-[4-(pyridin-3-yl)-1H-1,2,3-triazol-1-yl]phenyl}pyrimidin-4-ol

4-Chloro-2-(6-methoxypyrimidin-4-yl)aniline (0.1 g, 0.424 mmol) wasdissolved in ACN (5 mL) and cooled to 0° C. To this solution was addedisopentylnitrite ((0.075 g, 0.636 mmol) followed by the addition ofTMSN₃ (0.073 g, 0.636 mmol). The reaction mixture was stirred at 0° C.for 0.5 h then allowed to warm to rt and stirred overnight. To thesolution was added Cu₂₀ (6.1 mg, 0.042 mmol) followed by3-ethynylpyridine (0.044 g, 0.424 mmol) and stirred at rt. The reactionturned milky gray to clear in about 2 min. After 1 h, the reaction wasconcentrated and directly purified via a 12 g silica gel ISCO columnusing hexane/EtOAc as eluants to give6-{5-chloro-2-[4-(pyridin-3-yl)-1H-1,2,3-triazol-1-yl]phenyl}pyrimidin-4-ol(0.069 g) as a yellowish orange liquid. LCMS m/z 355.1 (M+H). ¹H NMR(500 MHz, CDCl₃) δ 8.89-8.86 (m, 1H), 7.91-7.88 (m, 1H), 7.49-7.45 (m,1H), 7.29 (s, 5H), 7.27-7.20 (m, 2H), 4.10-4.04 (m, 3H). The product wasdissolved in AcOH (1 mL) and 48% aq HBr (0.2 mL) was added, sealed andheated at 80° C. for 2 h. The reaction was concentrated and quenchedwith sat NaHCO₃ (25 mL) and extracted with EtOAc (2×25 mL). The organicextracts were combined, dried over MgSO₄, filtered and concentrated toafford6-{5-chloro-2-[4-(pyridin-3-yl)-1H-1,2,3-triazol-1-yl]phenyl}pyrimidin-4-olas an oil (0.011 g, 7% yield). LCMS m/z 351.1 (M+H).

215B. Preparation of(9R,13S)-13-(4-{5-chloro-2-[4-(pyridin-3-yl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate

(9R,13S)-13-(4-{5-Chloro-2-[4-(pyridin-3-yl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate was prepared (3.5 mg, 14.1%) following the proceduredescribed in Example 56 by using6-{5-chloro-2-[4-(pyridin-3-yl)-1H-1,2,3-triazol-1-yl]phenyl}pyrimidin-4-ol(12 mg, 0.034 mmol) and(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(11 mg, 0.034 mmol). LCMS m/z 668.1 (M+H). ¹H NMR (500 MHz, DMSO-d₆) δ9.45-9.41 (m, 1H), 9.13-9.09 (m, 1H), 9.02-8.97 (m, 1H), 8.69-8.62 (m,1H), 8.53-8.47 (m, 1H), 8.35-8.29 (m, 1H), 7.99-7.95 (m, 2H), 7.93-7.83(m, 4H), 7.75-7.70 (m, 1H), 7.64-7.59 (m, 1H), 7.55-7.50 (m, 1H),7.49-7.42 (m, 1H), 7.41-7.32 (m, 1H), 7.29-7.23 (m, 1H), 6.50-6.46 (m,1H), 5.71-5.59 (m, 1H), 2.55-2.29 (m, 2H), 1.99-1.81 (m, 2H), 1.54-1.39(m, 1H), 1.28-1.06 (m, 2H), 1.05-0.98 (d, 3H), 0.50-0.31 (m, 1H).Orthogonal RT. 1.652 purity>92%; Factor XIa Ki=0.48 nM, PlasmaKallikrein Ki=75 nM.

Example 216 Preparation of(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-4-(pyridin-3-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2,5,14,16-pentaen-8-one

(9R,13S)-13-{4-[5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one,prepared as described in Example 101, (0.09 g, 0.156 mmol),(1R,2R)—N1,N2-dimethylcyclohexane-1,2-diamine (0.022 g, 0.156 mmol),Cs₂CO₃ (0.102 g, 0.312 mmol), and 3-iodopyridine (0.032 g, 0.156 mmol)were added to a 5 mL microwave vial. DMF (2 mL) was added and the vialwas purged with Ar (3×). CuI (2 mg, 10.50 μmol) was added, the vial wassealed with a microwave vial cap and the reaction was heated in amicrowave reactor at 120° C. for 30 min. The reaction was then purifiedby reverse phase chromatography to yield(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-4-(pyridin-3-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2,5,14,16-pentaen-8-onetrifluoroacetate (52 mg, 42% yield) as a tan solid. MS(ESI) m/z: 653.6(M+H)⁺. ¹H NMR (400 MHz, CD₃OD) δ 9.34-9.21 (m, 1H), 8.81-8.73 (m, 1H),8.72-8.64 (m, 2H), 8.60 (s, 2H), 8.37 (s, 1H), 8.02-7.96 (m, 1H),7.96-7.89 (m, 1H), 7.87-7.80 (m, 1H), 7.80-7.73 (m, 2H), 7.72-7.63 (m,1H), 6.47-6.35 (m, 1H), 6.20-6.03 (m, 1H), 2.96-2.82 (m, 1H), 2.42-2.22(m, 2H), 2.17-2.01 (m, 1H), 1.83-1.70 (m, 1H), 1.70-1.52 (m, 1H),1.42-1.26 (m, 1H), 1.11 (d, J=7.0 Hz, 3H), 0.97-0.85 (m, 2H). AnalyticalHPLC (Method A): RT=6.69 min, purity=97.5%; Factor XIa Ki=0.57 nM,Plasma Kallikrein Ki=10 nM.

Example 217 Preparation of(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-3-(pyridin-3-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

(9R,13S)-13-{4-[5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-3-(pyridin-3-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate was synthesized as a minor product (24 mg, 19% yield)from the reaction to generate(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-4-(pyridin-3-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2,5,14,16-pentaen-8-one,Example 216. MS(ESI) m/z: 653.6 (M+H)⁺. ¹H NMR (400 MHz, CD₃OD) δ9.27-9.27 (m, 1H), 9.30-9.21 (m, 1H), 8.63 (s, 6H), 8.39 (s, 1H),8.17-8.09 (m, 1H), 7.95-7.90 (m, 1H), 7.88-7.83 (m, 1H), 7.82-7.73 (m,3H), 7.71-7.65 (m, 1H), 6.50-6.37 (m, 1H), 5.95-5.80 (m, 1H), 2.78-2.60(m, 1H), 2.55-2.39 (m, 1H), 2.15-1.98 (m, 2H), 1.83-1.65 (m, 1H),1.61-1.44 (m, 2H), 1.32 (d, J=7.0 Hz, 5H). Analytical HPLC (Method A):RT=6.45 min, purity=95%; Factor XIa Ki=74 nM, Plasma KallikreinK_(i)=600 nM.

Example 218 Preparation of(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-3-phenyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6])octadeca-1(18),2(6),4,14,16-pentaen-8-one

218A. Preparation of 4-nitro-1-phenyl-1H-pyrazole

To a 3-neck flask was added 4-nitro-1H-pyrazole (3.0 g, 26.5 mmol),phenylboronic acid (5.18 g, 42.4 mmol), NaOH (1.061 g, 26.5 mmol), CuCl₂(0.357 g, 2.65 mmol) and MeOH (25 mL). The above reaction mixture wasthen refluxed overnight while bubbling air through it. The solvent wasthen removed under vacuum and the crude product was purified by silicagel chromatography to yield 4-nitro-1-phenyl-1H-pyrazole (3.5 g, 17.58mmol, 66% yield) as a white solid. MS(ESI) m/z: 190.1 [M+H]⁺.

218B. Preparation of (S)-tert-butyl(1-(4-(4-nitro-1-phenyl-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate

To a N₂ flushed, 500 mL RBF was added (S)-tert-butyl(1-(4-chloropyridin-2-yl) but-3-en-1-yl)carbamate, prepared as describedin Intermediate 23, (2.5 g, 8.84 mmol), 4-nitro-1-phenyl-1H-pyrazole(1.67 g, 8.84 mmol) and dioxane (50 mL). The solution was bubbled withN₂ for 5 min and Pd(OAc)₂ (0.1 g, 0.442 mmol), di(adamantan-1-yl)(butyl)phosphine (0.317 g, 0.884 mmol), K₂CO₃ (3.67 g, 26.5 mmol) and PvOH(0.271 g, 0.265 mmol) were added. The reaction mixture was bubbled withN₂ for 5 min, then heated to 100° C. for 3 h. Water (200 mL) was added.The reaction mixture was extracted with EtOAc (2×200 mL). The combinedorganic extracts were washed with water (200 mL), brine (200 mL), driedover Na₂SO₄, filtered and concentrated. Purification by normal phasechromatography eluting with a gradient of hexanes/EtOAc afforded(S)-tert-butyl(1-(4-(4-nitro-1-phenyl-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate(3.0 g, 6.54 mmol, 74% yield) as a slightly yellow oil. MS(ESI) m/z:436.5 [M+H]⁺.

218C. Preparation of(9R,13S)-13-amino-9-methyl-3-phenyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

(9R,13S)-13-Amino-9-methyl-3-phenyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onewas prepared in the similar manner as described in Intermediate 30, byusing (S)-tert-butyl(1-(4-(4-nitro-1-phenyl-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate.(0.11 g, 0.34 mmol, 90% yield). MS(ESI) m/z: 362.5 [M+H]⁺.

218D.(9R,13S)-13-{4-[5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-3-phenyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate

(9R,13S)-13-{4-[5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-3-phenyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate (0.024 g, 0.030 mmol, 33% yield) was prepared in asimilar manner as the procedures described in Example 56, by using6-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol(0.028 g, 0.091 mmol), prepared as described in Intermediate 9, and(9R,13S)-13-amino-9-methyl-3-phenyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(0.033 g, 0.091 mmol). ¹H NMR (400 MHz, CD₃OD) δ 8.81 (s, 1H), 8.39 (d,J=5.3 Hz, 1H), 8.32 (s, 1H), 7.87 (d, J=2.4 Hz, 2H), 7.76-7.68 (m, 2H),7.65-7.60 (m, 1H), 7.51-7.38 (m, 5H), 6.66 (dd, J=5.1, 1.5 Hz, 1H), 6.37(s, 1H), 6.02 (dd, J=12.7, 4.3 Hz, 1H), 3.34 (s, 1H), 2.76 (td, J=6.5,3.1 Hz, 1H), 2.36-2.23 (m, 1H), 2.18-2.08 (m, 1H), 2.06-1.91 (m, 1H),1.74-1.56 (m, 1H), 1.55-1.39 (m, 1H), 1.02 (d, J=7.0 Hz, 3H), 0.65 (br.s., 1H). MS(ESI) m/z: 652.6 [M+H]⁺. Analytical HPLC (Method A): RT=9.41min, purity=>95.0%; Factor XIa Ki=83 nM, Plasma Kallikrein Ki=2,700 nM.

Example 219 Preparation of(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]pyridin-3-yl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

(9R,13S)-13-(4-{5-Chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]pyridin-3-yl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(4 mg, 3% yield) as a solid was prepared in via the coupling of6-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]pyridin-3-yl}pyrimidin-4-ol(0.014 g, 0.04 mmol) and(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one (0.014 g, 0.04 mmol) using the HATU, DBU couplingmethodology as described in Example 56. MS m/z=661.2 (M+H)⁺. ¹H NMR (400MHz, CD₃OD) δ 9.30-9.27 (m, 1H), 9.08-9.03 (m, 1H), 8.79 (s, 2H),8.37-8.33 (m, 1H), 7.78-7.74 (m, 2H), 7.70-7.67 (m, 1H), 7.59-7.51 (m,1H), 6.14-6.00 (m, 1H), 2.81-2.68 (m, 1H), 2.47-2.29 (m, 1H), 2.16-2.01(m, 2H), 1.70-1.46 (m, 2H), 1.07-0.96 (d, 3H), 0.75-0.55 (m, 1.H).Analytical HPLC (Method A) RT=11.3 min, purity=98%; Factor XIa Ki=35 nM,Plasma Kallikrein Ki=7,200 nM.

Example 220 Preparation of(9R,13S)-13-(5-bromo-4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]pyridin-3-yl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

(9R,13S)-13-(5-Bromo-4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]pyridin-3-yl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onewas isolated as a by-product of Example 219 (3 mg, 9% yield) as a solid,via the coupling of6-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]pyridin-3-yl}pyrimidin-4-olcontaining5-bromo-6-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]pyridin-3-yl}pyrimidin-4-ol(0.014 g, 0.04 mmol) and(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one (0.014 g, 0.04 mmol) using the HATU, DBU couplingmethodology as described in Example 56. MS m/z=740.4 (M+H)⁺. AnalyticalHPLC (Method A) RT=12.2 min, purity=93%; Factor XIa Ki=250 nM, PlasmaKallikrein Ki=7,000 nM.

Example 221 Preparation of(9R,13S)-13-(4-{5-chloro-4-fluoro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

(9R,13S)-13-(4-{5-Chloro-4-fluoro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(4 mg, 15% yield) as a solid was prepared via the coupling of6-{5-chloro-4-fluoro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}pyrimidin-4-ol(0.013 g, 0.036 mmol) and(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one (0.012 g, 0.036 mmol) using the HATU, DBU couplingmethodology as previously described. MS m/z=678.1 (M+H). ¹H NMR (400MHz, CD₃OD) δ 8.88-8.82 (m, 2H), 8.75-8.72 (m, 1H), 8.10-8.04 (m, 1H),7.76 (s, 2H), 7.72-7.65 (m, 1H), 7.56-7.51 (m, 1H), 6.46 (s, 1H),6.09-5.96 (m, 1H), 4.07-3.99 (m, 1H), 3.53-3.44 (m, 1H), 2.81-2.64 (m,1H), 2.37-2.21 (m, 1H), 2.09-1.96 (m, 2H), 1.68-1.42 (m, 2H), 1.02 (d,J=7.0 Hz, 3H); Factor XIa Ki=4.7 nM, Plasma Kallikrein Ki=1,300 nM.

Example 222 Preparation of(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-9-methyl-3-phenyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

(9R,13S)-13-(4-{5-Chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-9-methyl-3-phenyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate (4.5 mg, 0.005 mmol, 6% yield) was prepared in asimilar manner as the procedures described in Example 56, by using6-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}pyrimidin-4-ol(0.031 g, 0.091 mmol), prepared as described in Intermediate 15, and(9R,13S)-13-amino-9-methyl-3-phenyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(0.033 g, 0.091 mmol), prepared as described in Example 218C. ¹H NMR(400 MHz, CD₃OD) δ 8.80 (d, J=0.9 Hz, 1H), 8.77 (s, 1H), 8.37 (d, J=5.3Hz, 1H), 7.89 (d, J=2.2 Hz, 1H), 7.86 (s, 1H), 7.78-7.72 (m, 2H),7.71-7.66 (m, 1H), 7.50-7.39 (m, 5H), 6.66 (dd, J=5.1, 1.5 Hz, 1H), 6.45(d, J=0.7 Hz, 1H), 6.03 (dd, J=12.7, 4.3 Hz, 1H), 3.35 (s, 1H), 2.76(td, J=6.6, 3.1 Hz, 1H), 2.27 (tt, J=12.7, 4.5 Hz, 1H), 2.18-2.06 (m,1H), 2.05-1.92 (m, 1H), 1.70-1.55 (m, 1H), 1.54-1.41 (m, 1H), 1.03 (d,J=6.8 Hz, 3H), 0.66 (br. s., 1H). MS(ESI) m/z: 686.6 [M+H]⁺. AnalyticalHPLC (Method A): RT=10.03 min, purity=>95.0%; Factor XIa Ki=48 nM,Plasma Kallikrein Ki=3,700 nM.

Example 223 Preparation of(9R,13S)-13-(4-{4,5-dichloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

(9R,13S)-13-(4-{4,5-Dichloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(5 mg, 22% yield) as a solid was prepared via the coupling of6-{4,5-dichloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}pyrimidin-4-ol(0.012 g, 0.03 mmol) and(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(0.011 g, 0.03 mmol) using the HATU, DBU coupling methodology asdescribed in Example 56. MS m/z=694.1 (M+H)⁺. ¹H NMR (400 MHz, CD₃OD) δ8.88-8.83 (m, 2H), 8.75-8.71 (m, 1H), 8.10-8.08 (m, 1H), 8.02 (s, 1H),7.76 (s, 1H), 7.72-7.69 (m, 1H), 7.56-7.51 (m, 1H), 6.47 (d, J=0.7 Hz,1H), 6.08-6.00 (m, 1H), 2.80-2.63 (m, 1H), 2.36-2.16 (m, 1H), 2.11-1.96(m, 2H), 1.67-1.42 (m, 2H), 1.06-0.95 (d, 3H), 0.71-0.53 (m, 1H).Analytical HPLC (Method A) RT=13.3 min, purity=98%; Factor XIa Ki=11 nM,Plasma Kallikrein Ki=4,500 nM.

Example 224 Preparation of(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-4-(1-methyl-1H-imidazol-5-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2,5,14,16-pentaen-8-one

(9R,13S)-13-{4-[5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-4-(1-methyl-1H-imidazol-5-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2,5,14,16-pentaen-8-one(21 mg, 18%) as a peach solid was prepared in a similar manner as theprocedure described in Example 216, by using5-iodo-1-methyl-1H-imidazole. MS(ESI) m/z: 656.2 (M+H)⁺. ¹H NMR (400MHz, CD₃OD) δ 9.06-9.01 (m, 1H), 8.82-8.77 (m, 1H), 8.70-8.65 (m, 1H),8.37 (s, 1H), 8.22-8.20 (m, 1H), 7.99-7.97 (m, 1H), 7.97-7.94 (m, 1H),7.93-7.90 (m, 1H), 7.79-7.74 (m, 1H), 7.70-7.66 (m, 1H), 7.66-7.62 (m,1H), 6.42-6.38 (m, 1H), 6.17-6.06 (m, 1H), 3.98 (s, 3H), 2.94-2.83 (m,1H), 2.39-2.22 (m, 2H), 2.12-2.00 (m, 1H), 1.81-1.69 (m, 1H), 1.68-1.54(m, 1H), 1.13-1.05 (m, 3H), 0.87-0.74 (m, 1H). Analytical HPLC (MethodA): RT=5.81 min, purity=91%; Factor XIa Ki=4.5 nM, Plasma KallikreinKi=220 nM.

Example 225 Preparation of4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}-N-(2,2,2-trifluoroethyl)benzamide

225A. Preparation of4-chloro-2-(6-methoxypyrimidin-4-yl)-N-(2,2,2-trifluoroethyl) benzamide

To a RBF was added 4-chloro-2-(6-methoxypyrimidin-4-yl)benzoic acid(0.374 g, 1.413 mmol), prepared as described in Example 168B, EtOAc(7.07 ml), 2,2,2-CF₃CH₂NH₂ (0.14 g, 1.413 mmol), and pyridine (0.229 ml,2.83 mmol). The solution was cooled in a MeOH/ice bath and 50% w/w2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide inEtOAc (1.26 ml, 2.120 mmol) was added. The reaction was allowed to warmto rt. After 18 h, the reaction was diluted with EtOAc, washed with satNaHCO₃, brine, dried over Na₂SO₄, filtered, and concentrated. DCM (˜10ml) was added, plus a few drops of MeOH to afford a yellow suspension.The solid was filtered off, and the filtrate was purified by normalphase chromatography to afford4-chloro-2-(6-methoxypyrimidin-4-yl)-N-(2,2,2-trifluoroethyl)benzamide(0.155 g, 32% yield) as a white solid. MS(ESI) m/z: 346.4 (M+H)⁺.

225B. Preparation of4-chloro-2-(6-hydroxypyrimidin-4-yl)-N-(2,2,2-trifluoroethyl) benzamide

To a solution of4-chloro-2-(6-methoxypyrimidin-4-yl)-N-(2,2,2-trifluoroethyl) benzamide(0.05 g, 0.145 mmol) in ACN (0.96 ml) was added TMSI (0.118 ml, 0.868mmol). The reaction was heated to 50° C. After 6 h, the reaction wascooled to rt, poured into a 10% aq Na₂S₂O₃, and extracted with EtOAc(3×). The combined organic layers were washed with sat NaHCO₃, brine,dried over Na₂SO₄, filtered, and concentrated. Purification by normalphase chromatography afforded4-chloro-2-(6-hydroxypyrimidin-4-yl)-N-(2,2,2-trifluoroethyl)benzamide(0.02 g, 42% yield) as a white solid. MS(ESI) m/z: 332.3 (M+H)⁺. ¹H NMR(400 MHz, CD₃OD) δ 8.14 (d, J=0.9 Hz, 1H), 7.69 (d, J=2.0 Hz, 1H),7.59-7.55 (m, 1H), 7.54-7.49 (m, 1H), 6.63 (d, J=0.9 Hz, 1H), 3.98 (q,J=9.5 Hz, 2H). ¹⁹F NMR (376 MHz, CD₃OD) δ −73.22 (s).

225C. Preparation of4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}-N-(2,2,2-trifluoroethyl)benzamidetrifluoroacetate

4-Chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}-N-(2,2,2-trifluoroethyl)benzamidetrifluoroacetate (4.8 mg, 11% yield) was prepared in a similar manner asthe procedure described in Example 56, by replacing6-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}pyrimidin-4-olwith4-chloro-2-(6-hydroxypyrimidin-4-yl)-N-(2,2,2-trifluoroethyl)benzamide(0.02 g, 0.060 mmol). MS(ESI) m/z: 614.5 (M+H)⁺. ¹H NMR (400 MHz, CD₃OD)δ 8.95 (s, 1H), 8.73 (d, J=5.3 Hz, 1H), 7.72-7.71 (m, 2H), 7.59-7.55 (m,1H), 7.54-7.48 (m, 3H), 6.66 (s, 1H), 6.05 (dd, J=12.5, 4.2 Hz, 1H),4.08-3.90 (m, 5H), 2.76-2.67 (m, 1H), 2.39-2.28 (m, 1H), 2.15-1.98 (m,2H), 1.68-1.42 (m, 2H), 1.01 (d, J=7.0 Hz, 3H), 0.79-0.62 (m, 1H). ¹⁹FNMR (376 MHz, CD₃OD) δ −73.10 (s), −77.67 (s). Analytical HPLC (MethodA): RT=6.78 min, 98.2% purity; Factor XIa Ki=23 nM, Plasma KallikreinKi=3,400 nM.

Example 226 Preparation of(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-5,9-dimethyl-4,5,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),3,14,16-pentaen-8-one

226A. Preparation ofN-[(1S)-1-[4-(5-amino-1-methyl-1H-pyrazol-4-yl)pyridin-2-yl]but-3-en-1-yl]carbamate

In a microwave vial was added(S)-(2-(1-((tert-butoxycarbonyl)amino)but-3-en-1-yl)pyridin-4-yl)boronicacid (500 mg, 1.712 mmol), 4-bromo-1-methyl-1H-pyrazol-5-amine (301 mg,1.712 mmol), (DtBPF)PdCl₂ (55.8 mg, 0.086 mmol), 3 M K₃PO₄ (1.712 mL,5.13 mmol), and THF (18 mL). The reaction mixture was purged with Ar(3×), then heated at 130° C. in a microwave for 30 min The reactionmixture was then cooled to rt, diluted with EtOAc and washed with brine(2×15 mL). The crude product was then subjected to silica gelchromatography to yieldN-[(1S)-1-[4-(5-amino-1-methyl-1H-pyrazol-4-yl)pyridin-2-yl]but-3-en-1-yl]carbamate(0.5 g, 1.383 mmol, 81% yield). MS(ESI) m/z: 344.5 (M+H)⁺.

226B. Preparation of(9R,13S)-13-amino-5,9-dimethyl-4,5,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),3,14,16-pentaen-8-one

(9R,13S)-13-Amino-5,9-dimethyl-4,5,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),3,14,16-pentaen-8-one(83 mg, 0.263 mmol, 88% yield) was prepared in a similar manner as theprocedure described in Intermediate 32, by replacing Intermediate 32CwithN-[(1S)-1-[4-(5-amino-1-methyl-1H-pyrazol-4-yl)pyridin-2-yl]but-3-en-1-yl]carbamateand continuing through the rest of the sequence as described in thepreparation of Intermediate 32.

226C. Preparation of(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-5,9-dimethyl-4,5,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),3,14,16-pentaen-8-onetrifluoroacetate

(9R,13S)-13-{4-[5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-5,9-dimethyl-4,5,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),3,14,16-pentaen-8-onetrifluoroacetate (24 mg, 0.032 mmol, 34% yield) was prepared in asimilar manner as the procedure described in Example 56 by using6-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol(28.8 mg, 0.094 mmol), prepared as described in Intermediate 9, and(9R,13S)-13-amino-5,9-dimethyl-4,5,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),3,14,16-pentaen-8-one(28.0 mg, 0.094 mmol). ¹H NMR (400 MHz, CD₃OD) δ 8.56 (d, J=5.7 Hz, 2H),8.37 (s, 1H), 8.05 (br. s., 1H), 7.95 (br. s., 1H), 7.89 (d, J=2.4 Hz,1H), 7.78-7.71 (m, 1H), 7.69-7.61 (m, 2H), 6.40 (s, 1H), 5.94 (br. s.,1H), 3.82 (s, 3H), 2.88 (d, J=18.3 Hz, 1H), 2.36 (br. s., 1H), 2.29-2.07(m, 2H), 1.76 (d, J=7.3 Hz, 1H), 1.55 (br. s., 1H), 1.15 (br. s., 3H),1.00 (br. s., 1H). MS(ESI) m/z: 590.5 [M+H]⁺. Analytical HPLC (MethodA): RT=7.04 min, purity=>95.0%; Factor XIa Ki=106 nM.

Example 227 Preparation of(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-5,9-dimethyl-4,5,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),3,14,16-pentaen-8-one

(9R,13S)-13-(4-{5-Chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-5,9-dimethyl-4,5,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),3,14,16-pentaen-8-onetrifluoroacetate (21 mg, 0.027 mmol, 29% yield) was prepared in asimilar manner as the procedure described in Example 226 by replacing6-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol with6-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol(32.0 mg, 0.094 mmol), prepared as described in Intermediate 15. ¹H NMR(400 MHz, CD₃OD) δ 8.84 (s, 1H), 8.55-8.42 (m, 2H), 8.02 (br. s., 1H),7.97-7.86 (m, 2H), 7.78-7.71 (m, 1H), 7.70-7.59 (m, 2H), 6.44 (s, 1H),5.93 (br. s., 1H), 3.79 (s, 3H), 2.99-2.81 (m, 1H), 2.32 (br. s., 1H),2.26-2.04 (m, 2H), 1.73 (d, J=7.3 Hz, 1H), 1.52 (br. s., 1H), 1.26-1.07(m, 3H), 0.99 (br. s., 1H). MS(ESI) m/z: 624.5 [M+H]⁺. Analytical HPLC(Method A): RT=7.83 min, purity=>95.0%; Factor XIa Ki=97 nM.

Example 228 Preparation of(9R,13S)-13-[4-(1-benzyl-5-chloro-1H-indazol-7-yl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

228A. Preparation of 6-(1-benzyl-5-chloro-1H-indazol-7-yl)pyrimidin-4-ol

6-(1-Benzyl-5-chloro-1H-indazol-7-yl)pyrimidin-4-ol (32 mg, 32%) wasprepared in a similar manner as Intermediate 22 by replacing MeI withBnBr. MS(ESI) m/z: 337 (M+H)⁺ and 339 (M+2+H)⁺.

228B. Preparation of(9R,13S)-13-[4-(1-benzyl-5-chloro-1H-indazol-7-yl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate

(9R,13S)-13-[4-(1-Benzyl-5-chloro-1H-indazol-7-yl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate (4 mg, 9.7%) was prepared in a similar manner asExample 56 using 6-(1-benzyl-5-chloro-1H-indazol-7-yl)pyrimidin-4-ol and(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one,prepared as described in Intermediate 30. MS(ESI) m/z: 655 (M+H)⁺ and657 (M+2+H)⁺. ¹H NMR (400 MHz, methanol-d4) δ 8.99 (s, 1H), 8.69 (d,J=5.1 Hz, 1H), 8.47-8.39 (m, 1H), 8.28 (d, J=2.0 Hz, 1H), 8.11 (s, 1H),7.89-7.82 (m, 1H), 7.72 (d, J=13.6 Hz, 2H), 7.41 (d, J=5.1 Hz, 1H),7.35-7.21 (m, 4H), 6.05-5.94 (m, 1H), 5.65 (s, 2H), 2.65 (d, J=6.2 Hz,1H), 2.40-2.30 (m, 1H), 2.07-1.92 (m, 2H), 1.56-1.33 (m, 3H), 0.90 (d,J=7.0 Hz, 3H), 0.53 (br. s., 1H). Analytical HPLC (Method A): RT=10.76min, purity=>95%; Factor XIa Ki=110 nM.

Example 229 Preparation of(9R,13S)-13-{4-[5-chloro-2-(1H-1,2,3-triazol-1-yl)phenyl]-5-methyl-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

229A. Preparation of6-(5-chloro-2-(4-(trimethylsilyl)-1H-1,2,3-triazol-1-yl)phenyl)-5-methylpyrimidin-4-ol

6-(5-Chloro-2-(4-(trimethylsilyl)-1H-1,2,3-triazol-1-yl)phenyl)-5-methylpyrimidin-4-ol(53 mg, 50% yield) was prepared in a similar manner as the proceduredescribed in Intermediate 18C, by replacing1-[4-chloro-2-(6-methoxypyrimidin-4-yl)phenyl]-1H-1,2,3-triazole-4-carbonitrilewith4-(5-chloro-2-(4-(trimethylsilyl)-1H-1,2,3-triazol-1-yl)phenyl)-6-methoxy-5-methylpyrimidine(0.110 g, 0.294 mmol). MS(ESI) m/z: 560.4 (M+H)⁺.

229B. Preparation of6-(5-chloro-2-(1H-1,2,3-triazol-1-yl)phenyl)-5-methylpyrimidin-4-ol

To a solution of6-(5-chloro-2-(4-(trimethylsilyl)-1H-1,2,3-triazol-1-yl)phenyl)-5-methylpyrimidin-4-ol(53 mg, 0.147 mmol) in THF (5 mL) was added 1 M TBAF in THF (0.162 mL,0.162 mmol) at rt. After 3 h, the solution was concentrated andpartitioned between EtOAc and water and the layers were separated. Theaqueous layer was extracted with EtOAc (2×). The combined organic layerwas concentrated and then purified by normal phase chromatography togive 6-(5-chloro-2-(1H-1,2,3-triazol-1-yl)phenyl)-5-methylpyrimidin-4-ol(14 mg, 33% yield) as an orange glass. MS(ESI) m/z: 288.4 (M+H)⁺. ¹H NMR(400 MHz, CDCl₃) δ 8.02 (s, 1H), 7.71 (d, J=0.9 Hz, 1H), 7.64-7.58 (m,3H), 7.51 (t, J=1.3 Hz, 1H), 1.76 (s, 3H).

229C. Preparation of(9R,13S)-13-{4-[5-chloro-2-(1H-1,2,3-triazol-1-yl)phenyl]-5-methyl-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate

(9R,13S)-13-{4-[5-Chloro-2-(1H-1,2,3-triazol-1-yl)phenyl]-5-methyl-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate (13 mg, 37% yield) was prepared in a similar manner asthe procedure described in Example 56, by replacing6-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}pyrimidin-4-olwith 6-(5-chloro-2-(1H-1,2,3-triazol-1-yl)phenyl)-5-methylpyrimidin-4-ol(0.014 g, 0.049 mmol). MS(ESI) m/z: 570.1 (M+H)⁺. ¹H NMR (400 MHz,CD₃OD) δ8.89 (s, 1H), 8.76 (d, J=5.5 Hz, 1H), 8.17 (d, J=0.9 Hz, 1H),7.84 (s, 1H), 7.80-7.71 (m, 3H), 7.70-7.64 (m, 2H), 7.51 (s, 1H), 5.93(dd, J=12.5, 4.2 Hz, 1H), 4.07 (s, 3H), 2.70 (td, J=6.8, 3.3 Hz, 1H),2.36 (ddt, J=12.6, 8.4, 4.3 Hz, 1H), 2.14-2.00 (m, 2H), 1.69 (s, 3H),1.66-1.55 (m, 1H), 1.53-1.39 (m, 1H), 1.03 (d, J=7.0 Hz, 3H), 0.79 (m,1H). Analytical HPLC (Method A): RT=6.51 min, purity=99%; Factor XIaKi=63 nM, Plasma Kallikrein Ki=2,200 nM.

Example 230 Preparation of(9R,13S)-13-{4-[5-chloro-2-(1-methyl-1H-pyrazol-3-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

(9R,13S)-13-{4-[5-Chloro-2-(1-methyl-1H-pyrazol-3-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate (1.14 mg, 7% yield) was prepared in a similar manner asthe procedure described in Example 49, by replacing1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolewith1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(7.61 mg, 0.037 mmol). MS(ESI) m/z: 569.5 (M+H)⁺. ¹H NMR (400 MHz,CD₃OD) δ 8.91 (s, 1H), 8.71 (d, J=5.1 Hz, 1H), 7.87 (d, J=2.2 Hz, 1H),7.67 (s, 1H), 7.61 (dd, J=8.3, 2.3 Hz, 1H), 7.52-7.47 (m, 2H), 7.46-7.42(m, 2H), 6.26 (d, J=2.0 Hz, 1H), 6.13 (s, 1H), 6.00-5.92 (m, 1H), 4.04(s, 3H), 3.50 (s, 3H), 2.75-2.66 (m, 1H), 2.35-2.24 (m, 1H), 2.13-1.94(m, 2H), 1.65-1.42 (m, 2H), 1.00 (d, J=6.8 Hz, 3H), 0.76-0.60 (m, 1H).Analytical HPLC (Method A): RT=7.34 min, 98.4% purity; Factor XIa Ki=800nM.

Example 231 Preparation of(9R,13S)-13-{4-[5-chloro-2-(1H-imidazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

To the solution of 1H-imidazole (8.86 mg, 0.130 mmol) and(9R,13S)-13-[4-(5-chloro-2-iodophenyl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate (0.02 g, 0.033 mmol), prepared as described in Example211, in DMSO (1 ml) was added CuI (0.62 mg, 3.25 μmol), L-proline (0.75mg, 6.51 μmol), and K₂CO₃ (0.013 g, 0.098 mmol). The reaction was heatedat 80° C. for 3 h and cooled to rt. Purification by reverse phasechromatography afforded(9R,13S)-13-{4-[5-chloro-2-(1H-imidazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate (11 mg, 43% yield) as a yellow solid. MS(ESI) m/z:555.5 (M+H)⁺. ¹H NMR (500 MHz, CD₃OD) δ 9.19 (s, 1H), 8.77-8.67 (m, 2H),7.92 (d, J=2.5 Hz, 1H), 7.81-7.75 (m, 1H), 7.73-7.64 (m, 4H), 7.54-7.48(m, 2H), 6.62 (s, 1H), 6.00-5.91 (m, 1H), 4.04 (s, 3H), 2.74-2.64 (m,1H), 2.32-2.21 (m, 1H), 2.11-1.92 (m, 2H), 1.64-1.39 (m, 2H), 1.01 (d,J=6.9 Hz, 3H), 0.79-0.63 (m, 1H). Analytical HPLC (Method A): RT=4.41min, 99.9% purity; Factor XIa Ki=23 nM, Plasma Kallikrein Ki=1,100 nM.

Example 232 Preparation of(9R,13S)-13-[4-(5-chloro-1H-indazol-7-yl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

232A. Preparation of 6-(5-chloro-1H-indazol-7-yl)pyrimidin-4-ol

6-(5-Chloro-1H-indazol-7-yl)pyrimidin-4-ol (13.8 mg, 17%) was preparedin a similar manner to Example 207C starting from7-bromo-5-chloro-1H-indazole instead of4-bromo-6-chloro-1H-benzo[d]imidazole. MS(ESI) m/z: 247 (M+H)⁺ and 249(M+2+H)⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.41 (d, J=0.9 Hz, 1H), 8.15 (s,1H), 8.02 (d, J=1.8 Hz, 1H), 7.99 (d, J=1.8 Hz, 1H), 7.14 (d, J=0.7 Hz,1H).

232B. Preparation of(9R,13S)-13-[4-(5-chloro-1H-indazol-7-yl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3-(difluoromethymethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate

(9R,13S)-13-[4-(5-Chloro-1H-indazol-7-yl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate (5 mg, 13%) was prepared in a similar manner as Example56 using 6-(5-chloro-1H-indazol-7-yl)pyrimidin-4-ol and(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one,prepared as described in Intermediate 30. MS(ESI) m/z: 565 (M+H)⁺ and567 (M+2+H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 13.40 (br. s., 1H), 9.37 (s,1H), 9.00 (s, 1H), 8.70 (d, J=5.1 Hz, 1H), 8.14 (br. s., 1H), 8.07-8.02(m, 1H), 7.98 (d, J=1.5 Hz, 1H), 7.93-7.74 (m, 2H), 7.69 (s, 1H), 7.38(d, J=5.1 Hz, 1H), 7.19 (br. s., 1H), 5.93 (d, J=9.5 Hz, 1H), 2.65-2.60(m, 1H), 2.26 (d, J=1.8 Hz, 1H), 2.06-1.91 (m, 2H), 1.49-1.30 (m, 2H),0.83 (d, J=6.8 Hz, 3H), 0.35 (br. s., 1H). Analytical HPLC (Method A):RT=11.43 min, purity=>95%; Factor XIa Ki=110 nM, Plasma KallikreinKi=4,300 nM.

Example 233 Preparation of(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-4-(6-methoxypyridin-3-yl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2,5,14,16-pentaen-8-one

(9R,13S)-13-{4-[5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-4-(6-methoxypyridin-3-yl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2,5,14,16-pentaen-8-onewas prepared in a similar manner as the procedure described in Example216, by using 5-iodo-2-methoxypyridine to give(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-4-(6-methoxypyridin-3-yl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2,5,14,16-pentaen-8-onetrifluoroacetate as a brown solid (12 mg, 23%). MS(ESI) m/z: 683.5(M+H)⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.74-8.69 (m, 1H), 8.68-8.62 (m, 2H),8.36 (d, J=7.4 Hz, 2H), 8.21-8.14 (m, 1H), 8.02-7.97 (m, 1H), 7.92 (d,J=2.2 Hz, 1H), 7.75 (d, J=2.5 Hz, 2H), 7.67 (d, J=8.5 Hz, 1H), 7.01-6.94(m, 1H), 6.41 (d, J=0.8 Hz, 1H), 6.13-6.03 (m, 1H), 4.00 (s, 3H),2.90-2.81 (m, 1H), 2.38-2.22 (m, 2H), 2.05 (s, 1H), 1.81-1.69 (m, 1H),1.64-1.52 (m, 1H), 1.40-1.28 (m, 1H), 1.11 (d, J=6.9 Hz, 3H). AnalyticalHPLC (Method A): RT=9.08 min, purity=95%; Factor XIa Ki=1.1 nM, PlasmaKallikrein Ki=16 nM.

Example 234 Preparation of(1R,14S)-3-chloro-14-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-10-methyl-5,8-diazatricyclo[13.3.1.0²7]nonadeca-1(19),2(7),3,5,15,17-hexaen-9-one

(10R,14S)-3-Chloro-14-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-10-methyl-5,8-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-9-onetrifluoroacetate (0.0069 g, 44%) was prepared according to theprocedures described in Example 206 by using(10R,14S)-14-amino-3-chloro-10-methyl-5,8-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-9-one,prepared as described in Intermediate 38, by replacing2-bromopyridin-3-amine with 4-bromo-5-chloropyridin-3-amine inIntermediate 38B. MS(ESI) m/z: 620.1 (M+H)⁺. ¹H NMR (500 MHz, CD₃OD, 60°C.) δ 9.00 (s, 1H), 8.75 (s, 1H), 8.71-8.60 (m, 1H), 8.56 (s, 1H), 8.16(d, J=2.5 Hz, 1H), 8.03 (dd, J=8.4, 2.3 Hz, 1H), 7.97-7.82 (m, 4H), 7.73(br. s., 1H), 6.70 (s, 1H), 6.04 (dd, J=12.8, 3.2 Hz, 1H), 2.73-2.55 (m,2H), 2.52-2.41 (m, 1H), 2.00 (d, J=9.1 Hz, 2H), 1.85-1.58 (m, 1H), 1.47(d, J=6.6 Hz, 3H), 1.45-1.23 (m, 1H). Analytical HPLC (Method A):RT=9.14 min, purity>99%; Factor XIa Ki=0.29 nM, Plasma Kallikrein Ki=80nM.

Example 235 Preparation of(9R,13S)-13-{4-[5-chloro-2-(1H-pyrazol-4-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

(9R,13S)-13-{4-[5-Chloro-2-(1H-pyrazol-4-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate (2.97 mg, 14% yield) was prepared in a similar manneras the procedure described in Example 49, by replacing1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolewith tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate(14.35 mg, 0.049 mmol). MS(ESI) m/z: 555.5 (M+H)⁺. ¹H NMR (400 MHz,CD₃OD) δ 8.97 (s, 1H), 8.75 (d, J=5.1 Hz, 1H), 7.70 (s, 1H), 7.57-7.47(m, 7H), 6.37 (s, 1H), 6.02 (dd, J=12.5, 4.4 Hz, 1H), 4.05 (s, 3H),2.76-2.67 (m, 1H), 2.39-2.28 (m, 1H), 2.15-1.98 (m, 2H), 1.67-1.43 (m,2H), 1.01 (d, J=7.0 Hz, 3H), 0.80-0.63 (m, 1H). Analytical HPLC (MethodA): RT=6.50 min, 99.7% purity; Factor XIa Ki=14 nM, Plasma KallikreinKi=550 nM.

Example 236 Preparation ofN-benzyl-4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}benzamide

To a cooled (0° C.) solution of phenylmethanamine (0.081 ml, 0.741 mmol)in DCE (1.48 ml) was added dropwise a 2.0 M Al(Me)₃ in hexane (0.36 ml,0.72 mmol). A white plume of gas formed above the reaction mixture. Gasevolution was observed in the solution. The resulting clear solution wasstirred at 0° C. for 15 min, and then warmed to rt for 2 h. Next asolution of methyl4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}benzoate(0.049 g, 0.074 mmol), prepared as described in Example 168, in DCE (1ml) was added and the resulting clear, yellow reaction was heated to 40°C. After 5 h, the reaction was cooled to rt and the reaction was addedto a cold (0° C.), vigorously stirred suspension of DCM/sat Rochelle'ssalt. The biphasic mixture was stirred for 10-15 min and then the layerswere separated. The aqueous layer was extracted with DCM. The combinedorganic layers were washed with 1.0 N HCl, brine, dried over Na₂SO₄,filtered and concentrated. Purification by reverse phase chromatographyaffordedN-benzyl-4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}benzamidetrifluoroacetate (6 mg, 11% yield) as a yellow solid. MS(ESI) m/z: 622.6(M+H)⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.80 (s, 1H), 8.71 (d, J=5.1 Hz, 1H),7.72 (s, 1H), 7.69 (s, 1H), 7.55-7.49 (m, 4H), 7.34-7.15 (m, 5H), 6.66(s, 1H), 6.02 (dd, J=12.5, 4.2 Hz, 1H), 4.51-4.39 (m, 2H), 4.05 (s, 3H),2.78-2.67 (m, 1H), 2.34-2.21 (m, 1H), 2.16-2.05 (m, 1H), 2.03-1.92 (m,1H), 1.69-1.42 (m, 2H), 1.02 (d, J=6.8 Hz, 3H), 0.77-0.59 (m, 1H).Analytical HPLC (Method A): RT=7.27 min, 97.9% purity; Factor XIa Ki=23nM, Plasma Kallikrein Ki=1,600 nM.

Example 237 Preparation of(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-4-(pyridin-2-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2,5,14,16-pentaen-8-one

(9R,13S)-13-{4-[5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-4-(pyridin-2-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2,5,14,16-pentaen-8-onewas prepared in a similar manner as the procedure described in Example216, by using 2-iodopyridine to give(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-4-(pyridin-2-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2,5,14,16-pentaen-8-onetrifluoroacetate (44 mg, 47%). MS(ESI) m/z: 653.5 (M+H)⁺. ¹H NMR (500MHz, DMSO-d₆) δ 9.56-9.54 (m, 1H), 9.54 (s, 1H), 8.80 (s, 1H), 8.73-8.73(m, 1H), 8.75 (s, 1H), 8.68 (s, 1H), 8.64 (d, J=5.2 Hz, 1H), 8.53 (d,J=4.9 Hz, 1H), 8.12-8.02 (m, 2H), 8.00-7.90 (m, 2H), 7.88-7.81 (m, 1H),7.81-7.72 (m, 1H), 7.63 (dd, J=5.0, 1.1 Hz, 1H), 7.49-7.39 (m, 1H), 6.39(s, 1H), 6.12-5.95 (m, 1H), 2.88-2.73 (m, 1H), 2.40-2.22 (m, 2H),1.92-1.78 (m, 1H), 1.64-1.51 (m, 1H), 1.50-1.37 (m, 1H), 0.95 (d, J=6.7Hz, 3H), 0.65-0.40 (m, 1H). Analytical HPLC (Method C): RT=1.75 min,purity=100%; Factor XIa Ki=8 nM, Plasma Kallikrein Ki=150 nM.

Example 238 Preparation of1-(4-chloro-3-fluoro-2-{1-[(9R,13S)-3-(²H₃)methyl-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)-1H-pyrazole-4-carbonitrile

238A. Preparation of4-(3-chloro-2-fluoro-6-iodophenyl)-6-methoxypyrimidine

To a suspension of 4-chloro-3-fluoro-2-(6-methoxypyrimidin-4-yl)aniline(2 g, 7.88 mmol) in CH₃CN (90 ml) at 0° C. was added pTsOH.H₂O (3.75 g,19.71 mmol) followed by the dropwise addition of a solution of NaNO₂(1.088 g, 15.77 mmol) and NaI (2.95 g, 19.71 mmol) in water (22.5 ml).The reaction was allowed to warm to rt and stir overnight. The reactionwas quenched with sat NaHCO₃, and extracted with EtOAc. The organiclayer was washed with sat Na₂S₂O₃, brine, dried with MgSO₄, filtered,and concentrated. Purification by normal phase chromatography gave4-(3-chloro-2-fluoro-6-iodophenyl)-6-methoxypyrimidine (2.18 g, 76%yield) as viscous, yellow oil. MS(ESI) m/z: 365.1 (M+H)⁺. ¹H NMR (400MHz, CDCl₃) δ 8.92 (d, J=0.9 Hz, 1H), 7.68 (dd, J=8.4, 1.5 Hz, 1H), 7.20(dd, J=8.5, 7.4 Hz, 1H), 6.78 (s, 1H), 4.07 (s, 3H).

238B. Preparation of 6-(3-chloro-2-fluoro-6-iodophenyl)pyrimidin-4-ol

To a suspension of4-(3-chloro-2-fluoro-6-iodophenyl)-6-methoxypyrimidine (0.22 g, 0.603mmol) in ACN (6.03 ml) was added TMSI (0.411 ml, 3.02 mmol). Theresulting clear, yellow solution was heated to 50° C. for 15 h.Additional TMSI (0.4 ml) was added and the reaction was heated 50° C.for 7 h. The reaction was poured into a 10% Na₂S₂O₃ and sat NaHCO₃,extracted with EtOAc (2×), and a mixture of DCM and MeOH. The organiclayers were combined and concentrated. Purification by normal phasechromatography gave 6-(3-chloro-2-fluoro-6-iodophenyl)pyrimidin-4-ol(190 mg, 90% yield) as a yellow glass. MS(ESI) m/z: 351.1 (M+H)⁺. ¹H NMR(400 MHz, CD₃OD) δ 8.33 (d, J=1.1 Hz, 1H), 7.77 (dd, J=8.6, 1.5 Hz, 1H),7.34 (dd, J=8.6, 7.5 Hz, 1H), 6.51 (d, J=0.9 Hz, 1H), 4.85 (br. s., 1H).

238C. Preparation of1-(4-chloro-3-fluoro-2-(6-hydroxypyrimidin-4-yl)phenyl)-1H-pyrazole-4-carbonitrile

To a suspension of 1H-pyrazole-4-carbonitrile (50.5 mg, 0.542 mmol),K₃PO₄ (233 mg, 1.084 mmol) and6-(3-chloro-2-fluoro-6-iodophenyl)pyrimidin-4-ol (190 mg, 0.542 mmol) indioxane (0.24 mL) was added(1R,2R)—N1,N2-dimethylcyclohexane-1,2-diamine (38.6 mg, 0.271 mmol). Thevial was then purged with Ar, CuI (5.16 mg, 0.027 mmol) was added, andthe vial was sealed. The reaction mixture was heated at 80° C. After 16h, the reaction was cooled to rt, filtered, and the filtrate wasconcentrated. Purification by reverse phase chromatography gave1-(4-chloro-3-fluoro-2-(6-hydroxypyrimidin-4-yl)phenyl)-1H-pyrazole-4-carbonitrile(74 mg, 43% yield) as an off-white solid. MS(ESI) m/z: 316.3 (M+H)⁺. ¹HNMR (400 MHz, CD₃OD) δ 8.54 (s, 1H), 8.09 (d, J=0.9 Hz, 1H), 7.97 (s,1H), 7.80 (dd, J=8.7, 7.8 Hz, 1H), 7.50 (dd, J=8.7, 1.7 Hz, 1H), 6.51(t, J=1.1 Hz, 1H).

238D. Preparation of1-(4-chloro-3-fluoro-2-{1-[(9R,13S)-3-(²H₃)methyl-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)-1H-pyrazole-4-carbonitrile,trifluoroacetate

1-(4-Chloro-3-fluoro-2-{1-[(9R,13S)-3-(²H₃)methyl-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)-1H-pyrazole-4-carbonitriletrifluoroacetate (9.5 mg, 41% yield) was prepared in a similar manner asthe procedure described in Example 56, by using1-(4-chloro-3-fluoro-2-(6-hydroxypyrimidin-4-yl)phenyl)-1H-pyrazole-4-carbonitrile(10 mg, 0.032 mmol) and(9R,13S)-13-amino-3-(²H₃)methyl-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(9.58 mg, 0.032 mmol), prepared as described in Intermediate 33. MS(ESI)m/z: 601.0 (M+H)⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.81 (s, 1H), 8.76 (d,J=5.1 Hz, 1H), 8.46 (s, 1H), 7.94 (s, 1H), 7.80 (dd, J=8.6, 7.7 Hz, 1H),7.69 (s, 1H), 7.55-7.48 (m, 3H), 6.54 (s, 1H), 6.00 (dd, J=13.0, 4.2 Hz,1H), 2.70 (dt, J=6.7, 3.2 Hz, 1H), 2.36-2.25 (m, 1H), 2.15-1.95 (m, 2H),1.67-1.55 (m, 1H), 1.55-1.41 (m, 1H), 1.01 (d, J=6.8 Hz, 3H), 0.72 (m.,1H). Analytical HPLC (Method A): RT=7.58 min, purity=98.5%; Factor XIaKi=2.4 nM, Plasma Kallikrein Ki=1,500 nM.

Example 239 Preparation of1-(4-chloro-2-{1-[(9R,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}-3-fluorophenyl)-1H-pyrazole-4-carbonitrile

1-(4-Chloro-2-{1-[(9R,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}-3-fluorophenyl)-1H-pyrazole-4-carbonitrilewas prepared in a similar manner as the procedure described in Example238, by replacing(9R,13S)-13-amino-3-(²H₃)methyl-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one,prepared as described in Intermediate 33, with(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(10.62 mg, 0.032 mmol), prepared as described in Example 30G. MS(ESI)m/z: 634.0 (M+H)⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.86 (s, 1H), 8.78 (d,J=5.1 Hz, 1H), 8.47 (s, 1H), 7.94 (s, 1H), 7.83-7.77 (m, 1H), 7.74 (s,1H), 7.70 (s, 1H), 7.65 (s, 1H), 7.52 (dd, J=8.7, 1.4 Hz, 2H), 6.55 (s,1H), 6.01 (dd, J=12.7, 4.1 Hz, 1H), 2.76-2.65 (m, 1H), 2.31 (t, J=13.0Hz, 1H), 2.10-1.95 (m, 2H), 1.65-1.42 (m, 2H), 1.00 (d, J=7.0 Hz, 3H),0.67 (m., 1H). Analytical HPLC (Method A): SunFire, RT=8.75 min, 98.8%purity; Factor XIa Ki=1.0 nM, Plasma Kallikrein Ki=1,100 nM.

Example 240 Preparation of(9R,13S)-13-{4-[5-chloro-2-(1-propyl-1H-pyrazol-4-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

(9R,13S)-13-{4-[5-Chloro-2-(1-propyl-1H-pyrazol-4-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate (14.3 mg, 62% yield) was prepared in a similar manneras the procedure described in Example 49, by replacing1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolewith1-propyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(11.52 mg, 0.049 mmol). MS(ESI) m/z: 597.4 (M+H)⁺. ¹H NMR (400 MHz,CD₃OD) δ 9.01 (s, 1H), 8.75 (d, J=5.1 Hz, 1H), 7.74 (s, 1H), 7.58-7.52(m, 3H), 7.50-7.47 (m, 3H), 7.42 (s, 1H), 6.40 (d, J=0.4 Hz, 1H), 6.02(dd, J=12.7, 4.3 Hz, 1H), 4.07-4.01 (m, 5H), 2.76-2.67 (m, 1H),2.40-2.29 (m, 1H), 2.13-2.00 (m, 2H), 1.77 (sxt, J=7.2 Hz, 2H),1.67-1.43 (m, 2H), 1.02 (d, J=6.8 Hz, 3H), 0.79 (t, J=7.4 Hz, 3H),0.75-0.66 (m, 1H). Analytical HPLC (Method A): RT=8.12 min, 100% purity;Factor XIa Ki=35 nM, Plasma Kallikrein Ki=3,800 nM.

Example 241 Preparation of(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-4-(pyridin-4-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2,5,14,16-pentaen-8-one

(9R,13S)-13-{4-[5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-4-(pyridin-4-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2,5,14,16-pentaen-8-onewas prepared in a similar manner as the procedure described in Example216, by using 4-iodopyridine to give(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-4-(pyridin-4-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2,5,14,16-pentaen-8-onetrifluoroacetate (29 mg, 30% yield). MS(ESI) m/z: 653.6 (M+H)⁺. ¹H NMR(500 MHz, DMSO-d₆) δ 9.57 (s, 1H), 8.86 (s, 1H), 8.72 (s, 1H), 8.67 (s,1H), 8.58 (d, J=4.9 Hz, 1H), 8.04 (br. s., 2H), 7.91-7.82 (m, 2H),7.80-7.73 (m, 1H), 7.73-7.65 (m, 1H), 7.57 (d, J=5.2 Hz, 1H), 6.31 (s,1H), 6.01-5.87 (m, 1H), 2.80-2.67 (m, 1H), 2.22 (d, J=7.3 Hz, 2H), 1.80(br. s., 1H), 1.59-1.45 (m, 1H), 1.44-1.29 (m, 1H), 0.87 (d, J=7.0 Hz,3H), 0.59-0.36 (m, 1H). Analytical HPLC (Method C): RT=1.42 min,purity=98%; Factor XIa Ki=0.58 nM, Plasma Kallikrein Ki=20 nM.

Example 242 Preparation of(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-3-(pyridin-4-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

(9R,13S)-13-{4-[5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-3-(pyridin-4-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onewas synthesized as a minor product (2 mg, 2.4%) from the reaction togenerate(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-4-(pyridin-4-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2,5,14,16-pentaen-8-one,Example 241. MS(ESI) m/z: 653.6 (M+H)⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 8.98(br. s., 1H), 8.74 (br. s., 2H), 8.65 (br. s., 3H), 8.03-7.91 (m, 3H),7.88-7.66 (m, 5H), 6.41 (br. s., 1H), 5.91-5.79 (m, 1H), 3.90 (br. s.,1H), 3.45 (br. s., 2H), 2.41-2.30 (m, 2H), 2.10-2.04 (m, 1H), 2.03-1.95(m, 1H), 1.94-1.81 (m, 2H), 1.67 (br. s., 2H), 1.54 (br. s., 3H), 1.30(br. s., 4H), 1.21 (br. s., 4H). Analytical HPLC (Method C): RT=1.37min, purity=100%; Factor XIa Ki=22 nM, Plasma Kallikrein Ki=470 nM.

Example 243 Preparation of1-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)-1H-imidazole-4-carbonitrile

1-(4-Chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)-1H-imidazole-4-carbonitriletrifluoroacetate (9.7 mg, 37% yield) was prepared in a similar manner asthe procedure described in Example 231, by replacing 1H-imidazole with1H-imidazole-4-carbonitrile (0.012 g, 0.130 mmol). MS(ESI) m/z: 580.20(M+H)⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 9.22 (s, 1H), 8.82 (s, 1H), 8.69 (d,J=5.2 Hz, 1H), 8.29 (s, 1H), 8.04 (s, 1H), 7.88 (d, J=2.4 Hz, 1H), 7.78(dd, J=8.5, 2.1 Hz, 1H), 7.70-7.66 (m, 2H), 7.59 (d, J=4.9 Hz, 1H), 7.48(s, 1H), 6.37 (s, 1H), 5.89 (d, J=10.7 Hz, 1H), 4.01 (s, 3H), 2.69-2.61(m, 1H), 2.39-2.27 (m, 1H), 2.11 (t, J=12.5 Hz, 1H), 1.89-1.80 (m, 1H),1.53-1.42 (m, 1H), 1.39-1.29 (m, 1H), 0.89 (d, J=7.0 Hz, 3H), 0.50-0.34(m, 1H). Analytical HPLC (Method B): RT=8.12 min, 100% purity; FactorXIa Ki=53 nM, Plasma Kallikrein Ki=3,400 nM.

Example 244 Preparation ofN-(4-chloro-2-{1-[(9R,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)-2,2,2-trifluoroacetamide

N-(4-Chloro-2-{1-[(9R,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)-2,2,2-trifluoroacetamidewas prepared in a similar manner as the procedure described in Example56, usingN-(4-chloro-2-(6-hydroxypyrimidin-4-yl)phenyl)-2,2,2-trifluoroacetamide(0.19 g, 0.60 mmol), prepared as described in Intermediate 1, and(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(0.20 g, 0.60 mmol), prepared as described in Intermediate 30, to giveN-(4-chloro-2-{1-[(9R,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)-2,2,2-trifluoroacetamide(222 mg, 58%) as white powder. MS(ESI) m/z: 636.5 (M+H)⁺. ¹H NMR (400MHz, CD₃OD) δ 9.23 (s, 1H), 8.89 (s, 1H), 8.56 (d, J=5.1 Hz, 1H),7.74-7.69 (m, 3H), 7.55 (s, 1H), 7.46-7.39 (m, 1H), 7.24 (d, J=5.1 Hz,1H), 6.74 (s, 1H), 5.83-5.70 (m, 1H), 2.55-2.40 (m, 1H), 2.27-2.12 (m,1H), 1.89 (s, 1H), 1.81-1.66 (m, 1H), 1.38-1.24 (m, 1H), 1.24-1.11 (m,1H), 0.70 (d, J=7.0 Hz, 3H). Analytical HPLC (Method A): RT=10.89 min,purity=99%; Factor XIa Ki=3.9 nM, Plasma Kallikrein Ki=260 nM.

Example 245 Preparation of(9R,13S)-13-(4-{5-chloro-2-[1-(propan-2-yl)-1H-pyrazol-4-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

(9R,13S)-13-(4-{5-Chloro-2-[1-(propan-2-yl)-1H-pyrazol-4-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate (15.5 mg, 67% yield) was prepared in a similar manneras the procedure described in Example 49, by replacing1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolewith1-isopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(11.52 mg, 0.049 mmol). MS(ESI) m/z: 597.4 (M+H)⁺. ¹H NMR (400 MHz,CD₃OD) δ 9.02 (s, 1H), 8.75 (d, J=5.1 Hz, 1H), 7.74 (s, 1H), 7.62 (s,1H), 7.56 (dd, J=5.2, 1.7 Hz, 1H), 7.54-7.52 (m, 1H), 7.50-7.47 (m, 3H),7.39 (s, 1H), 6.40 (d, J=0.4 Hz, 1H), 6.02 (dd, J=12.7, 4.3 Hz, 1H),4.46 (spt, J=6.7 Hz, 1H), 4.05 (s, 3H), 2.76-2.66 (m, 1H), 2.41-2.30 (m,1H), 2.14-2.00 (m, 2H), 1.67-1.37 (m, 8H), 1.02 (d, J=6.8 Hz, 3H),0.80-0.64 (m, 1H). Analytical HPLC (Method A): RT=8.07 min, 100% purity;Factor XIa Ki=44 nM, Plasma Kallikrein Ki=5,600 nM.

Example 246 Preparation of(9R,13S)-13-{4-[5-(difluoromethoxy)-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

(9R,13S)-13-{4-[5-(Difluoromethoxy)-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(13 mg, 60% yield) as a solid was prepared via the coupling of6-[5-(difluoromethoxy)-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl]pyrimidin-4-ol(0.012 g, 0.03 mmol) and(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one (0.011 g, 0.03 mmol) using the HATU, DBU couplingmethodology as described in Example 56. MS m/z=692.1 (M+H)⁺. ¹H NMR (500MHz, DMSO-d₆) δ 9.39 (s, 1H), 9.22 (s, 1H), 8.78 (s, 1H), 8.70 (d, J=5.2Hz, 1H), 7.97-7.81 (m, 1H), 7.71-7.64 (m, 2H), 7.59-7.53 (m, 2H),7.50-7.46 (m, 1H), 7.45-7.41 (m, 1H), 6.47-6.41 (m, 1H), 5.95-5.85 (m,1H), 2.71-2.59 (m, 1H), 2.35-2.23 (m, 1H), 2.07-1.98 (m, 1H), 1.90-1.74(m, 1H), 1.52-1.24 (m, 2H), 0.88 (d, J=6.7 Hz, 3H), 0.46-0.19 (m, 1H).Analytical HPLC (Method B) RT=1.8 min, purity=100%; Factor XIa Ki=110nM.

Example 247 Preparation of(9R,13S)-3-(difluoromethyl)-13-(4-{5-methoxy-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

(9R,13S)-3-(Difluoromethyl)-13-(4-{5-methoxy-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(12 mg, 50% yield) as a solid was prepared via the coupling of6-{5-methoxy-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}pyrimidin-4-ol(0.012 g, 0.03 mmol) and(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one (0.012 g, 0.03 mmol) using the HATU, DBU couplingmethodology as described in Example 56. MS m/z=656.2 (M+H)⁺. ¹H NMR (500MHz, DMSO-d₆) δ 9.16-9.12 (m, 1H), 8.91-8.88 (m, 1H), 8.52-8.48 (m, 1H),8.47-8.43 (m, 1H), 7.66-7.63 (m, 2H), 7.60-7.55 (m, 1H), 7.46-7.42 (m,1H), 7.20-7.16 (m, 1H), 7.14-7.10 (m, 1H), 7.05-7.00 (m, 1H), 6.21-6.12(m, 1H), 5.72-5.54 (m, 1H), 2.46-2.38 (m, 1H), 2.09-1.98 (m, 1H),1.86-1.69 (m, 1H), 1.63-1.47 (m, 1H), 1.29-1.00 (m, 2H), 0.65-0.58 (d,3H), 0.20-0.04 (m, 1H). Analytical HPLC (Method B) RT=1.72 min,purity=100%; Factor XIa Ki=7.7 nM, Plasma Kallikrein Ki=2,400 nM.

Example 248 Preparation of(9R,13S)-13-(4-{5-chloro-2-[1-(2-methylpropyl)-1H-pyrazol-4-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

(9R,13S)-13-(4-{5-Chloro-2-[1-(2-methylpropyl)-1H-pyrazol-4-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate (7.6 mg, 32% yield) was prepared in a similar manner asthe procedure described in Example 49, by replacing1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolewith1-isobutyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(12.20 mg, 0.049 mmol). MS(ESI) m/z: 611.4 (M+H)⁺. ¹H NMR (400 MHz,CD₃OD) δ 9.00 (s, 1H), 8.75 (d, J=5.3 Hz, 1H), 7.72 (s, 1H), 7.57-7.47(m, 6H), 7.42 (s, 1H), 6.37 (d, J=0.4 Hz, 1H), 6.02 (dd, J=12.8, 4.2 Hz,1H), 4.05 (s, 3H), 3.91-3.81 (m, 2H), 2.76-2.67 (m, 1H), 2.34 (tt,J=12.7, 4.3 Hz, 1H), 2.14-1.98 (m, 3H), 1.67-1.43 (m, 2H), 1.01 (d,J=6.8 Hz, 3H), 0.83-0.63 (m, 7H). Analytical HPLC (Method A): RT=8.63min, 100% purity; Factor XIa Ki=73 nM, Plasma Kallikrein Ki=8,900 nM.

Example 249 Preparation of(9R,13S)-13-{4-[2-(1-benzyl-1H-pyrazol-4-yl)-5-chlorophenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

(9R,13S)-13-{4-[2-(1-Benzyl-1H-pyrazol-4-yl)-5-chlorophenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate (2.68 mg, 11% yield) was prepared in a similar manneras the procedure described in Example 49, by replacing1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolewith1-benzyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(13.86 mg, 0.049 mmol). MS(ESI) m/z: 645.4 (M+H)⁺. ¹H NMR (400 MHz,CD₃OD) δ 8.95 (s, 1H), 8.67 (d, J=5.1 Hz, 1H), 7.70 (s, 1H), 7.59 (s,1H), 7.54-7.45 (m, 6H), 7.29-7.19 (m, 3H), 7.09-7.05 (m, 2H), 6.36 (d,J=0.7 Hz, 1H), 6.00 (dd, J=12.7, 4.1 Hz, 1H), 5.27 (s, 2H), 4.02 (s,3H), 2.77-2.68 (m, 1H), 2.34-2.23 (m, 1H), 2.15-2.05 (m, 1H), 2.01-1.90(m, 1H), 1.67-1.42 (m, 2H), 1.02 (d, J=6.8 Hz, 3H), 0.76-0.60 (m, 1H).Analytical HPLC (Method A): RT=8.90 min, 100% purity; Factor XIa Ki=100nM.

Example 250 Preparation of(9R,13S)-13-{4-[5-chloro-2-(1-methyl-1H-1,2,3-triazol-4-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

250A. Preparation of 4-(5-chloro-2-ethynylphenyl)-6-methoxypyrimidine

A flame-dried flask containing4-(5-chloro-2-iodophenyl)-6-methoxypyrimidine (0.520 g, 1.50 mmol),prepared as described in Example 211, and Pd(PPh₃)₄ (0.087 g, 0.075mmol) was purged with Ar for several min. Next, degassed THF (7.50 ml)and tributylstannylacetylene (0.651 ml, 2.25 mmol) were added. Theresulting clear, burgundy solution was stirred at rt. After 15 h, thedark purple reaction was diluted with EtOAc and washed with brine, driedover Na₂SO₄, filtered and concentrated to give a purple solid.Purification by normal phase chromatography, using 0-10% EtOAc/Hex, gave4-(5-chloro-2-ethynylphenyl)-6-methoxypyrimidine (0.176 g, 48%) as anoff-white solid. MS(ESI) m/z: 244.9 (M+H)⁺.

250B. Preparation of4-(5-chloro-2-{1-[(trimethylsilyl)methyl]-1H-1,2,3-triazol-4-yl}phenyl)-6-methoxypyrimidine

A sealed vial containing a mixture of TMSN₃ (0.091 ml, 0.61 mmol),4-(5-chloro-2-ethynylphenyl)-6-methoxypyrimidine (0.050 g, 0.20 mmol),sodium ascorbate (8.10 mg, 0.041 mmol), and CuSO₄ (3.26 mg, 0.020 mmol)was stirred at 60° C. After 2 h, the dark black reaction was cooled tort. The mixture was diluted with EtOAc (15 mL), and the turbid solutionwas washed water (3×), brine, dried over Na₂SO₄, filtered andconcentrated to give 0.110 g of crude product as a black oil.Purification by normal phase chromatography using 0-40% EtOAc/Hex, gave4-(5-chloro-2-{1-[(trimethylsilyl)methyl]-1H-1,2,3-triazol-4-yl}phenyl)-6-methoxypyrimidine (0.0191 g,25%) as a yellow residue. MS(ESI) m/z: 374.0 (M+H)⁺.

250C. Preparation of4-[5-chloro-2-(1-methyl-1H-1,2,3-triazol-4-yl)phenyl]-6-methoxypyrimidine

To a cooled (0° C.) clear yellow solution of4-(5-chloro-2-(1-((trimethylsilyl)methyl)-1H-1,2,3-triazol-4-yl)phenyl)-6-methoxypyrimidine (0.019 g,0.051 mmol) in THF (0.508 ml) and water (1.831 μl, 0.102 mmol) was addeddropwise 1.0 M TBAF in THF (0.061 ml, 0.061 mmol). The reaction wasstirred at 0° C. for 1 h and then warmed to rt. After 2 h, additional1.0 M TBAF in THF (0.061 ml, 0.061 mmol) was added. After 51 h,additional 1.0 M TBAF in THF (0.51 ml, 0.51 mmol) was added. After 44 h,the reaction was diluted with EtOAc and washed with sat NH₄Cl, brine,dried over Na₂SO₄, filtered and concentrated to give4-(5-chloro-2-(1-methyl-1H-1,2,3-triazol-4-yl)phenyl)-6-methoxypyrimidine(0.015 g, 98%) as a yellow residue. MS(ESI) m/z: 302.0 (M+H)⁺.

250D. Preparation of6-[5-chloro-2-(1-methyl-1H-1,2,3-triazol-4-yl)phenyl]pyrimidin-4-ol

A clear, yellow solution of4-(5-chloro-2-(1-methyl-1H-1,2,3-triazol-4-yl)phenyl)-6-methoxypyrimidine(0.015 g, 0.050 mmol) in AcOH (0.50 ml) and 48% aq HBr (0.28 ml, 2.486mmol) was warmed to 85° C. After 1 h, the reaction was cooled to rt andthen concentrated to give a brown solid. The brown solid was suspendedin EtOAc and filtered to give and off-white solid. Purification byreverse phase chromatography gave, after free-basing with sat NaHCO₃,6-[5-chloro-2-(1-methyl-1H-1,2,3-triazol-4-yl) phenyl]pyrimidin-4-ol(0.0090 g, 63%) as a white solid. MS(ESI) m/z: 288.0 (M+H)⁺. ¹H NMR (500MHz, CD₃OD) δ 8.21 (s, 1H), 7.90 (s, 1H), 7.72 (d, J=8.3 Hz, 1H), 7.60(d, J=2.2 Hz, 1H), 7.58 (dd, J=8.3, 2.2 Hz, 1H), 6.38 (s, 1H), 4.09 (s,3H).

250E. Preparation of(9R,13S)-13-{4-[5-chloro-2-(1-methyl-1H-1,2,3-triazol-4-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate

(9R,13S)-13-{4-[5-Chloro-2-(1-methyl-1H-1,2,3-triazol-4-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate (0.0055 g, 25%) was prepared in a similar manner as theprocedure described in Example 56, by replacing6-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}pyrimidin-4-olwith6-[5-chloro-2-(1-methyl-1H-1,2,3-triazol-4-yl)phenyl]pyrimidin-4-ol.MS(ESI) m/z: 570.1 (M+H)⁺ and 572.0 (M+2+H)⁺. ¹H NMR (500 MHz, CD₃OD) δ8.94 (s, 1H), 8.75 (d, J=5.2 Hz, 1H), 7.90 (s, 1H), 7.74 (s, 1H), 7.70(d, J=8.3 Hz, 1H), 7.63 (d, J=2.2 Hz, 1H), 7.59-7.54 (m, 2H), 7.50 (s,1H), 6.40 (d, J=0.6 Hz, 1H), 6.04-5.99 (m, 1H), 4.08 (s, 3H), 4.05 (s,3H), 2.76-2.67 (m, 1H), 2.40-2.29 (m, 1H), 2.15-2.01 (m, 2H), 1.68-1.56(m, 1H), 1.55-1.43 (m, 1H), 1.02 (d, J=7.2 Hz, 3H), 0.79-0.64 (m, 1H).Analytical HPLC (Method A): RT=6.30 min, purity=100%; Factor XIa Ki=11nM, Plasma Kallikrein Ki=2,000 nM.

Example 251 Preparation of(10R,14S)-14-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-4-fluoro-10-methyl-5,8,16-triazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-9-one

251A. Preparation of tert-butyl N-(6-fluoro-4-iodopyridin-3-yl)carbamate

BuLi (11.31 ml, 28.3 mmol) was added dropwise to a stirred, cooled (−78°C.) solution of tert-butyl (6-fluoropyridin-3-yl)carbamate (2 g, 9.42mmol) and TMEDA (4.27 ml, 28.3 mmol) in Et₂O (47.1 ml). The mixture wasallowed to warm to −10° C. and stirred for 2 h. The mixture was recooledto −78° C. and a cooled (−10° C.) solution of 12 (4.90 g, 19.32 mmol) inEt₂O (25 mL) was added dropwise. The mixture was allowed to warm to rtand stirred for 2 days. Sat aq NH₄Cl was added and the mixture wasextracted with Et₂O and EtOAc. The combined organic fractions werewashed with Na₂S₂O₃, brine, dried over MgSO₄, filtered and concentratedto give a brownish oil, which was purified by normal phasechromatography to give tert-butylN-(6-fluoro-4-iodopyridin-3-yl)carbamate (0.859 g, 27% yield). MS(ESI)m/z: 338.9 (M+H)⁺.

251B. Preparation of 6-fluoro-4-iodopyridin-3-amine

To a solution of N-(6-fluoro-4-iodopyridin-3-yl)carbamate (400 mg, 1.183mmol) in DCM (15 mL) was added TFA (4.56 mL, 59.2 mmol). The reactionwas stirred at rt for 1 h. Concentration gave6-fluoro-4-iodopyridin-3-amine.trifluoroacetate (551 mg, 100%) as a paleyellow solid. MS(ESI) m/z: 238.9 (M+H)⁺.

251C. Preparation of(10R,14S)-14-amino-4-fluoro-10-methyl-5,8,16-triazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2,4,6,15,17-hexaen-9-one

(10R,14S)-14-Amino-4-fluoro-10-methyl-5,8,16-triazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2,4,6,15,17-hexaen-9-onewas prepared in a similar manner as the procedure described inIntermediate 39, by replacing 2-bromopyridin-3-amine with6-fluoro-4-iodopyridin-3-amine. MS(ESI) m/z: 315.4 (M+H)⁺.

251D. Preparation of(10R,14S)-14-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-4-fluoro-10-methyl-5,8,16-triazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-9-one

(10R,14S)-14-(4-{5-Chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-4-fluoro-10-methyl-5,8,16-triazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-9-onetrifluoroacetate (7.3 mg, 33.7% yield) was prepared in a similar manneras the procedure described in Example 56 by using

(10R,14S)-14-amino-4-fluoro-10-methyl-5,8,16-triazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2,4,6,15,17-hexaen-9-one(8.8 mg, 0.028 mmol). ¹H NMR (400 MHz, CD₃OD) δ 8.91 (s, 1H), 8.83-8.79(m, 1H), 8.71 (d, J=5.1 Hz, 1H), 8.13-8.09 (m, 1H), 7.89 (d, J=2.4 Hz,1H), 7.78-7.65 (m, 3H), 7.48 (dd, J=5.1, 1.8 Hz, 1H), 7.37 (d, J=2.2 Hz,1H), 6.42 (d, J=0.7 Hz, 1H), 6.04 (dd, J=12.5, 4.8 Hz, 1H), 2.79-2.65(m, 1H), 2.27-2.14 (m, 1H), 2.07-1.92 (m, 2H), 1.60-1.37 (m, 2H), 0.95(d, J=6.8 Hz, 3H), 0.57 (br. s., 1H). MS(ESI) m/z: 639.0 (M+H)⁺.Analytical HPLC (Method A): RT=9.64 min, purity=100%; Factor XIa Ki=0.53nM, Plasma Kallikrein Ki=71 nM.

Example 252 Preparation of(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-4-(6-methoxypyridin-2-yl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2,5,14,16-pentaen-8-one

(9R,13S)-13-(4-{5-Chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-4-(6-methoxypyridin-2-yl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2,5,14,16-pentaen-8-one(9.5 mg, 17%) was prepared in a similar manner as the proceduredescribed in Example 216, by using 2-iodo-6-methoxypyridine (31 mg,0.131 mmol) and(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(0.04 g, 0.066 mmol), as described in Example 196. MS(ESI) m/z: 717.4(M+H)⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 9.57 (s, 1H), 9.21 (s, 1H), 8.71 (d,J=15.6 Hz, 2H), 8.59 (d, J=5.2 Hz, 1H), 8.03-7.90 (m, 3H), 7.90-7.74 (m,2H), 7.68-7.49 (m, 2H), 6.83 (d, J=7.9 Hz, 1H), 6.50 (s, 1H), 6.01 (br.s., 1H), 3.98 (s, 3H), 2.79 (br. s., 1H), 2.38-2.15 (m, 2H), 1.85 (br.s., 1H), 1.58 (br. s., 1H), 1.42 (br. s., 1H), 0.95 (d, J=6.7 Hz, 3H),0.57 (br. s., 1H). Analytical HPLC (Method C): RT=2.07 min, purity=100%;Factor XIa K_(i)=23 nM, Plasma Kallikrein Ki=1,100 nM.

Example 253 Preparation of(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-4-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2,5,14,16-pentaen-8-one

(9R,13S)-13-(4-{5-Chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one,prepared as described in Example 196, (0.02 g, 0.033 mmol), sodium2-chloro-2,2-difluoroacetate (50 mg, 0.33 mmol), Cs₂CO₃ (0.021 g, 0.066mmol), and DMF (2 mL) were added to a 5 mL microwave vial. The reactionwas heated to 130° C. for 30 min in a microwave. The mixture wasconcentrated to dryness and the residue was purified by reverse phasechromatography to give(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-4-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2,5,14,16-pentaen-8-one(2 mg, 8%). MS(ESI) m/z: 660.1 (M+H)⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 9.54(s, 1H), 9.21 (s, 1H), 8.70 (s, 1H), 8.58 (d, J=4.9 Hz, 1H), 8.41 (s,1H), 7.96 (br. s., 1H), 7.92-7.68 (m, 4H), 7.53 (d, J=4.9 Hz, 1H), 6.49(s, 1H), 6.12-5.90 (m, 1H), 2.85-2.69 (m, 1H), 2.24 (d, J=11.9 Hz, 2H),1.89-1.76 (m, 1H), 1.63-1.49 (m, 1H), 1.47-1.35 (m, 1H), 0.92 (d, J=6.7Hz, 3H), 0.61-0.38 (m, 1H). Analytical HPLC (Method C): RT=1.82 min,purity=100%; Factor XIa Ki=8 nM, Plasma Kallikrein Ki=360 nM.

Example 254 Preparation of(9R,13S)-13-{4-[5-chloro-2-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

(9R,13S)-13-{4-[5-Chloro-2-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate (10 mg, 43% yield) was prepared in a similar manner asthe procedure described in Example 49, by replacing1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolewith1-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(11.42 mg, 0.049 mmol). MS(ESI) m/z: 595.4 (M+H)⁺. ¹H NMR (400 MHz,CD₃OD) δ 8.99 (s, 1H), 8.76 (d, J=5.3 Hz, 1H), 7.73 (s, 1H), 7.64 (s,1H), 7.57-7.52 (m, 2H), 7.50 (s, 1H), 7.47-7.46 (m, J=1.1 Hz, 2H), 7.33(d, J=0.7 Hz, 1H), 6.39 (s, 1H), 6.03 (dd, J=12.5, 4.2 Hz, 1H), 4.05 (s,3H), 3.63-3.56 (m, 1H), 2.76-2.67 (m, 1H), 2.35 (tt, J=12.7, 4.3 Hz,1H), 2.14-2.01 (m, 2H), 1.67-1.44 (m, 2H), 1.04-0.97 (m, 7H), 0.79-0.64(m, 1H). Analytical HPLC (Method A): RT=7.82 min, 99.9% purity; FactorXIa Ki=8 nM, Plasma Kallikrein Ki=1,700 nM.

Example 255 Preparation of(9R,13S)-13-(4-{5-chloro-2-[1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

255A. Preparation of4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazole

To a stirred solution of4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (100 mg,0.515 mmol) in DMF (1 ml) were added Cs₂CO₃ (252 mg, 0.773 mmol) and2,2,2-trifluoroethyl trifluoromethanesulfonate (0.144 ml, 1.031 mmol) atrt. After stirring at 100° C. for 2 h, the reaction mixture wasevaporated to dryness, partitioned between EtOAc and water, and thelayers were separated. The organic layer was dried over Na₂SO₄,filtered, and concentrated to afford4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazole(0.111 g, 78% yield). MS(ESI) m/z: 277.4 (M+H)⁺.

255B. Preparation of(9R,13S)-13-(4-{5-chloro-2-[1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate

(9R,13S)-13-(4-{5-Chloro-2-[1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate (10.6 mg, 43% yield) was prepared in a similar manneras the procedure described in Example 49, by replacing1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolewith4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazole(13.47 mg, 0.049 mmol), prepared as described in Example 255A. MS(ESI)m/z: 637.5 (M+H)⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.97 (s, 1H), 8.74 (d,J=5.3 Hz, 1H), 7.74-7.67 (m, 2H), 7.56-7.49 (m, 6H), 6.40 (s, 1H), 6.03(dd, J=12.7, 4.3 Hz, 1H), 4.92-4.82 (m, 2H), 4.05 (s, 3H), 2.76-2.67 (m,1H), 2.39-2.28 (m, 1H), 2.14-1.99 (m, 2H), 1.67-1.43 (m, 2H), 1.02 (d,J=7.0 Hz, 3H), 0.79-0.64 (m, 1H). Analytical HPLC (Method A): RT=8.26min, 99.5% purity; Factor XIa Ki=52 nM, Plasma Kallikrein Ki=5,500 nM.

Example 256 Preparation of3-[(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2,5,14,16-pentaen-4-yl]benzonitrile

3-[(9R,13S)-13-{4-[5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2,5,14,16-pentaen-4-yl]benzonitriletrifluoroacetate was prepared in a similar manner as the proceduredescribed in Example 216, by using 3-iodobenzonitrile (3.97 mg, 0.017mmol) to give3-[(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2,5,14,16-pentaen-4-yl]benzonitriletrifluoroacetate (4.5 mg, 33% yield). ¹H NMR (500 MHz, DMSO-d₆) δ 9.60(s, 1H), 8.76-8.65 (m, 2H), 8.60 (d, J=5.2 Hz, 1H), 8.36 (s, 1H), 8.25(d, J=8.2 Hz, 1H), 7.93-7.86 (m, 2H), 7.84-7.69 (m, 4H), 7.63 (d, J=4.3Hz, 1H), 6.34 (s, 1H), 5.98 (br. s., 1H), 2.78 (br. s., 1H), 2.54 (s,1H), 2.24 (d, J=7.3 Hz, 2H), 1.85 (br. s., 1H), 1.56 (br. s., 1H), 1.41(br. s., 1H), 0.93 (d, J=6.7 Hz, 3H), 0.55 (br. s., 1H). MS(ESI) m/z:677.1 [M+H]⁺. Analytical HPLC (Method B): RT=1.91 min, purity=100.0%;Factor XIa Ki=2.0 nM, Plasma Kallikrein Ki=30 nM.

Example 257 Preparation of(9R,13S)-13-{4-[5-chloro-2-(5-methyl-1H-imidazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate

(9R,13S)-13-{4-[5-Chloro-2-(5-methyl-1H-imidazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate (2.3 mg, 9% yield) was prepared in a similar manner asthe procedure described in Example 231, by replacing 1H-imidazole with4-methyl-1H-imidazole (10.68 mg, 0.130 mmol). MS(ESI) m/z: 569.20(M+H)⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 9.22 (s, 1H), 8.89 (br. s., 1H),8.78 (s, 1H), 8.67 (d, J=4.9 Hz, 1H), 8.01 (d, J=2.4 Hz, 1H), 7.86 (dd,J=8.5, 2.1 Hz, 1H), 7.75 (d, J=8.5 Hz, 1H), 7.66 (s, 1H), 7.59 (d, J=4.9Hz, 1H), 7.50-7.40 (m, 2H), 6.41 (br. s., 1H), 5.86 (d, J=10.4 Hz, 1H),4.01 (s, 3H), 2.68-2.60 (m, 1H), 2.32-2.22 (m, 1H), 2.16-2.05 (m, 1H),2.01 (s, 3H), 1.88-1.76 (m, 1H), 1.52-1.27 (m, 2H), 0.88 (d, J=6.7 Hz,3H), 0.50-0.37 (m, 1H). Analytical HPLC (Method B): RT=1.49 min, 100%purity; Factor XIa Ki=7,500 nM.

Example 258 Preparation of(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-4-(1H-pyrazol-3-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2,5,14,16-pentaen-8-one

(9R,13S)-13-{4-[5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-4-(1H-pyrazol-3-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2,5,14,16-pentaen-8-onetrifluoroacetate was prepared in a similar manner as the proceduredescribed in Example 216, by using 3-iodo-1-trityl-1H-pyrazole (18.9 mg,0.043 mmol) followed by deprotection using 50% TFA in DCM and Et₃SiH asa scavenger to yield(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-4-(1H-pyrazol-3-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2,5,14,16-pentaen-8-onetrifluoroacetate (4.8 mg, 3.2 μmol, 6% yield). ¹H NMR (500 MHz, DMSO-d₆)δ 9.45 (s, 1H), 8.76-8.69 (m, 1H), 8.57 (d, J=4.9 Hz, 1H), 8.31 (s, 1H),8.10 (br. s., 1H), 7.93 (d, J=2.1 Hz, 1H), 7.88 (s, 1H), 7.82 (dd,J=8.5, 2.1 Hz, 1H), 7.77-7.70 (m, 1H), 7.52 (d, J=4.9 Hz, 1H), 7.30-7.02(m, 3H), 6.37 (s, 1H), 5.97 (br. s., 1H), 2.76 (br. s., 1H), 2.27 (d,J=10.7 Hz, 2H), 1.84 (br. s., 1H), 1.55 (br. s., 1H), 1.41 (br. s., 1H),0.93 (d, J=6.7 Hz, 3H), 0.56 (br. s., 1H). MS(ESI) m/z: 642.3 [M+H]⁺.Analytical HPLC (Method B): RT=1.51 min, purity=100.0%; Factor XIaKi=0.29 nM, Plasma Kallikrein Ki=18 nM.

Example 259 Preparation of(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-4-(pyrimidin-5-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2,5,14,16-pentaen-8-one

(9R,13S)-13-{4-[5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-4-(pyrimidin-5-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2,5,14,16-pentaen-8-onetrifluoroacetate was prepared in a similar manner as the proceduredescribed in Example 216, by using 5-iodopyrimidine (21.4 mg, 0.104mmol) to give(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-4-(pyrimidin-5-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2,5,14,16-pentaen-8-onetrifluoroacetate (15 mg, 36%). ¹H NMR (400 MHz, CD₃OD) δ 9.58 (s, 1H),9.40 (s, 2H), 9.20 (s, 1H), 8.85-8.72 (m, 3H), 8.64 (d, J=5.3 Hz, 1H),7.98-7.91 (m, 2H), 7.87-7.80 (m, 1H), 7.79-7.73 (m, 1H), 7.65 (dd,J=5.1, 1.3 Hz, 1H), 6.39 (s, 1H), 6.02 (d, J=9.5 Hz, 1H), 2.82 (br. s.,1H), 2.37-2.23 (m, 2H), 1.94-1.80 (m, 1H), 1.58 (br. s., 1H), 1.43 (br.s., 1H), 0.99-0.91 (d, J=7.0 Hz, 3H), 0.56 (br. s., 1H). MS(ESI) m/z:654.6 [M+H]⁺. Analytical HPLC (Method A): RT=7.96 min, purity=>95.0%;Factor XIa Ki=0.63 nM, Plasma Kallikrein Ki=17 nM.

Example 260 Preparation of(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-9-methyl-4-(pyrazin-2-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2,5,14,16-pentaen-8-one

(9R,13S)-13-(4-{5-Chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-9-methyl-4-(pyrazin-2-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2,5,14,16-pentaen-8-onetrifluoroacetate (9.0 mg, 34%) was prepared in a similar manner as theprocedure described in Example 216, by using 2-iodopyrazine (6.75 mg,0.033 mmol) and(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one (20.0 mg, 0.033 mmol), as described inExample 196. ¹H NMR (500 MHz, DMSO-d₆) δ 9.60 (s, 1H), 9.33 (s, 1H),9.22 (s, 1H), 8.76-8.65 (m, 2H), 8.63-8.56 (m, 2H), 7.95 (d, J=16.5 Hz,2H), 7.88-7.78 (m, 2H), 7.66 (d, J=4.9 Hz, 1H), 7.27-6.98 (m, 1H), 6.49(s, 1H), 6.03 (d, J=9.5 Hz, 1H), 2.79 (br. s., 1H), 2.37-2.18 (m, 2H),1.83 (br. s., 1H), 1.56 (br. s., 1H), 1.42 (br. s., 1H), 0.93 (d, J=6.7Hz, 3H), 0.52 (br. s., 1H). MS(ESI) m/z: 688.0 [M+H]⁺. Analytical HPLC(Method B): RT=1.923 min, purity=>100.0%; Factor XIa Ki=2.6 nM, PlasmaKallikrein Ki=54 nM.

Example 261 Preparation of(9R,13S)-13-[4-(2-amino-5-chlorophenyl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

N-(4-Chloro-2-{1-[(9R,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)-2,2,2-trifluoroacetamide,prepared as described in Example 244, (0.2 g, 0.31 mmol) was dissolvedin 1.25 M HCl in MeOH (5 ml, 6.25 mmol). The reaction was heated to 75°C. for 1 h, then cooled to rt and concentrated to dryness. The productwas purified by recrystallizing from CH₃CN—H₂O to give(9R,13S)-13-[4-(2-amino-5-chlorophenyl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(160 mg, 89%) as a yellow solid. MS(ESI) m/z: 540.5 (M+H)⁺. ¹H NMR (500MHz, DMSO-d₆) δ 9.40 (s, 1H), 9.00 (s, 1H), 8.75 (d, J=5.09 Hz, 1H),7.96 (t, J=57.75 Hz, 1H), 7.90 (s, 1H), 7.73 (s, 1H), 7.46 (d, J=2.49Hz, 1H), 7.43 (dd, J=4.92, 0.85 Hz, 1H), 7.14 (dd, J=8.80, 2.51 Hz, 1H),6.76 (d, J=8.73 Hz, 1H), 6.70 (s, 1H), 6.43 (s, 2H), 5.95 (dd, 12.17,3.13 Hz, 1H), 2.67 (m, 1H), 2.34 (tm, J=12.83 Hz, 1H), 2.08 (tm, J=13.09Hz, 1H), 1.93 (m, 1H), 1.48 (m, 1H), 1.37 (m, 1H), 0.89 (d, J=6.87 Hz,3H), 0.39 (br-s, 1H). Analytical HPLC (Method A): RT=7.75 min,purity=94%; Factor XIa Ki=170 nM, Plasma Kallikrein Ki=5,700 nM.

Example 262 Preparation of(9R,13S)-13-(4-{3-chloro-6-[1-(difluoromethyl)-1H-pyrazol-4-yl]-2-fluorophenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

262A. Preparation of6-(3-chloro-6-(1-(difluoromethyl)-1H-pyrazol-4-yl)-2-fluorophenyl)pyrimidin-4-ol

6-(3-Chloro-6-(1-(difluoromethyl)-1H-pyrazol-4-yl)-2-fluorophenyl)pyrimidin-4-ol(0.032 g, 85% yield) was prepared in a similar manner as the proceduresdescribed in Example 140A and 140B, by replacing4-(2-bromo-5-chlorophenyl)-6-methoxypyrimidine (0.08 g, 0.267 mmol) with4-(6-bromo-3-chloro-2-fluorophenyl)-6-methoxypyrimidine (0.1 g, 0.315mmol). MS(ESI) m/z: 341.4 (M+H)⁺. ¹H NMR (500 MHz, CD₃OD) δ 8.35 (s,1H), 8.06 (s, 1H), 7.67-7.60 (m, 2H), 7.45 (t, J=59.4 Hz, 1H), 7.40 (dd,J=8.3, 1.4 Hz, 1H), 6.52 (s, 1H).

262B. Preparation of(9R,13S)-13-(4-{3-chloro-6-[1-(difluoromethyl)-1H-pyrazol-4-yl]-2-fluorophenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate

(9R,13S)-13-(4-{3-Chloro-6-[1-(difluoromethyl)-1H-pyrazol-4-yl]-2-fluorophenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate (11.7 mg, 36% yield) was prepared in a similar manneras the procedure described in Example 56, by replacing6-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}pyrimidin-4-ol(22.8 mg, 0.067 mmol) with6-(3-chloro-6-(1-(difluoromethyl)-1H-pyrazol-4-yl)-2-fluorophenyl)pyrimidin-4-ol(14.79 mg, 0.043 mmol). MS(ESI) m/z: 623.6 (M+H)⁺. ¹H NMR (500 MHz,CD₃OD) δ 8.99 (s, 1H), 8.75 (d, J=5.2 Hz, 1H), 8.00 (s, 1H), 7.73 (s,1H), 7.64-7.58 (m, 2H), 7.55-7.28 (m, 4H), 6.51 (s, 1H), 6.04 (dd,J=12.7, 3.9 Hz, 1H), 4.05 (s, 3H), 2.75-2.67 (m, 1H), 2.36 (tt, J=12.7,4.3 Hz, 1H), 2.13-2.02 (m, 2H), 1.66-1.45 (m, 2H), 1.02 (d, J=7.2 Hz,3H), 0.83-0.66 (m, 1H). ¹⁹F NMR (471 MHz, CD₃OD) δ −77.75 (s), −96.25(s), −117.96 (s). Analytical HPLC (Method A): RT=8.18 min, 98.0% purity;Factor XIa Ki=4.5 nM, Plasma Kallikrein Ki=340 nM.

Example 263 Preparation of(9R,13S)-13-[4-(5-chloro-1H-indol-7-yl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

263A. Preparation of 6-(5-chloro-1H-indol-7-yl)pyrimidin-4-ol

6-(5-Chloro-1H-indol-7-yl)pyrimidin-4-ol was prepared in a similarmanner as described for Example 207C by replacing4-bromo-6-chloro-1H-benzo[d]imidazole with 7-bromo-5-chloro-1H-indole.MS(ESI) m/z: 246 (M+H)⁺.

263B.(9R,13S)-13-[4-(5-Chloro-1H-indol-7-yl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate

(9R,13S)-13-[4-(5-Chloro-1H-indol-7-yl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate was prepared (0.61 mg, 1.3%) in a similar manner asdescribed in Example 56 by using6-(5-chloro-1H-indol-7-yl)pyrimidin-4-ol and(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one,prepared as described in Intermediate 30. MS(ESI) m/z: 564 (M+H)⁺ and566 (M+2+H)⁺. Analytical HPLC (Method A): RT=9.71 min, purity=>90%;Factor XIa Ki=4,600 nM.

Example 264 Preparation of(9R,13S)-13-[4-(6-chloro-1H-indazol-4-yl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

264A. Preparation of 6-(6-chloro-1H-indazol-4-yl)pyrimidin-4-ol

6-(6-Chloro-1H-indazol-4-yl)pyrimidin-4-ol was prepared in a similarmanner as described for Example 207C by replacing4-bromo-6-chloro-1H-benzo[d]imidazole with 4-bromo-6-chloro-1H-indazole.MS(ESI) m/z: 247 (M+H)⁺.

264B. Preparation of(9R,13S)-13-[4-(6-chloro-1H-indazol-4-yl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate

(9R,13S)-13-[4-(6-Chloro-1H-indazol-4-yl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate (4 mg, 9.4%) was prepared in a similar manner asExample 56 by using 6-(6-chloro-1H-indazol-4-yl)pyrimidin-4-ol and(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one,prepared as described in Intermediate 30. MS(ESI) m/z: 565 (M+H)⁺. ¹HNMR (400 MHz, DMSO-d₆) δ 9.35 (s, 1H), 9.05 (s, 1H), 8.69 (d, J=5.3 Hz,1H), 8.53 (s, 1H), 7.90-7.84 (m, 2H), 7.75-7.68 (m, 4H), 7.40-7.35 (m,2H), 7.02 (s, 1H), 2.62-2.58 (m, 1H), 2.36-2.30 (m, 1H), 2.06-2.01 (m,1H), 1.93-1.87 (m, 1H), 1.47-1.42 (m, 1H), 1.34-1.29 (m, 1H), 0.83 (d,J=6.8 Hz, 3H). Analytical HPLC (Method A): RT=7.32 min, purity=95%;Factor XIa Ki=260 nM.

Example 265 Preparation of(14S)-14-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-10-methyl-5,8,16-triazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-9-onetrifluoroacetate

265A. Preparation of(S)-(2-(1-((tert-butoxycarbonyl)amino)but-3-en-1-yl)pyridin-4-yl)boronicacid, trifluoroacetate

To a solution of 5,5,5′,5′-tetramethyl-2,2′-bi(1,3,2-dioxaborinane)(1.198 g, 5.30 mmol) and (S)-tert-butyl(1-(4-chloropyridin-2-yl)but-3-en-1-yl)carbamate (1.0 g, 3.54 mmol),prepared as described in Intermediate 23, in DMSO (10 mL) was added KOAc(1.041 g, 10.61 mmol) under Ar. PdCl₂(dppf)CH₂Cl₁₂ adduct (0.289 g,0.354 mmol) and the mixture was purged with Ar for an additional 10 minthen stirred at 85° C. After 12 h, the reaction mixture was diluted withEtOAc and washed with water. The aqueous layer was extracted with EtOAc.The combined organic layers were washed with brine, dried over Na₂SO₄,filtered, and concentrated. The dark oil purified by reverse phasechromatography to give, after concentration and lyophilization,(S)-(2-(1-((tert-butoxycarbonyl)amino)but-3-en-1-yl)pyridin-4-yl)boronicacid trifluoroacetate (1.05 g, 2.59 mmol, 73.1% yield) as a white solid.MS(ESI) m/z: 293.2 (M+H)⁺.

265B. Preparation of (S)-tert-butyl(1-(3′-amino-[4,4′-bipyridin]-2-yl)but-3-en-1-yl) carbamate

To a solution of(S)-(2-(1-((tert-butoxycarbonyl)amino)but-3-en-1-yl)pyridin-4-yl)boronicacid, trifluoroacetate (1.0 g, 2.462 mmol) and 4-bromopyridin-3-amine(0.511 g, 2.95 mmol) in dioxane (17 mL) was added 2 M aq Na₂CO₃ (4.92mL, 9.85 mmol). The mixture was purged with a stream of Ar for 5 min.Pd(PPh₃)₄ (0.285 g, 0.246 mmol) was added and the reaction wasirradiated at 120° C. for 1 h. The reaction was quenched with water (40mL) and extracted with EtOAc (2×). The combined organic layers werewashed with brine, dried over MgSO₄, filtered, and concentrated. Thecrude material was purified by normal phase column chromatographyeluting with a gradient of DCM/MeOH to give (S)-tert-butyl(1-(3′-amino-[4,4′-bipyridin]-2-yl)but-3-en-1-yl)carbamate (0.736 g, 88%yield) as a brown oil. MS(ESI) m/z: 341.2 (M+H)⁺. ¹H NMR (500 MHz,CDCl₃) δ 8.68 (d, J=4.7 Hz, 1H), 8.19 (s, 1H), 8.10 (d, J=5.0 Hz, 1H),7.35 (s, 1H), 7.29 (dd, J=5.1, 1.5 Hz, 1H), 7.02 (d, J=5.0 Hz, 1H),5.79-5.68 (m, 1H), 5.62-5.52 (m, 1H), 5.11-5.04 (m, 2H), 4.90-4.80 (m,1H), 3.83 (br. s., 2H), 2.64 (t, J=6.7 Hz, 2H), 1.45 (s, 9H).

265C. Preparation of tert-butyl((S)-1-(3′-((R)-2-methylbut-3-enamido)-[4,4′-bipyridin]-2-yl)but-3-en-1-yl)carbamate

To a solution of (S)-tert-butyl(1-(3′-amino-[4,4′-bipyridin]-2-yl)but-3-en-1-yl) carbamate (736 mg,2.16 mmol) in EtOAc (21.6 mL) was added (R)-2-methylbut-3-enoic acid(303 mg, 3.03 mmol). After cooling to 0° C., pyridine (0.525 mL, 6.49mmol) was added followed by T3P®/50% EtOAc (2.57 mL, 4.32 mmol)dropwise. The reaction was slowly warmed to rt overnight. The reactionmixture was diluted with water and extracted with EtOAc (2×). Thecombined organic layers were washed with brine, dried over MgSO₄,filtered, and concentrated. The crude material was purified by normalphase column chromatography eluting with a gradient of DCM/MeOH to giveof tert-butyl((S)-1-(3′-((R)-2-methylbut-3-enamido)-[4,4′-bipyridin]-2-yl)but-3-en-1-yl)carbamate (815 mg, 89%). MS(ESI) m/z: 423.2 (M+H)⁺. ¹H NMR (500 MHz,CDCl₃) δ 9.45 (s, 1H), 8.70 (d, J=5.0 Hz, 1H), 8.49 (d, J=5.0 Hz, 1H),7.24 (br. s., 1H), 7.21 (s, 1H), 7.18-7.14 (m, 2H), 5.80 (ddd, J=17.1,10.1, 8.3 Hz, 1H), 5.74-5.66 (m, 1H), 5.54-5.48 (m, 1H), 5.15-5.05 (m,4H), 4.92-4.85 (m, 1H), 3.08 (quin, J=7.2 Hz, 1H), 2.69-2.61 (m, 2H),1.45 (s, 9H), 1.31-1.28 (m, 3H).

265D. Preparation of tert-butylN-[(11E,14S)-10-methyl-9-oxo-5,8,16-triazatricyclo[13.3.1.0²7]nonadeca-1 (19),2(7),3,5,11,15,17-heptaen-14-yl]carbamate

To a solution oftert-butyl((S)-1-(3′-((R)-2-methylbut-3-enamido)-[4,4′-bipyridin]-2-yl)but-3-en-1-yl)carbamate(400 mg, 0.947 mmol) in freshly opened and degassed DCM (500 mL) wasadded p-TsOH.H₂O (378 mg, 1.988 mmol). A stream of N₂ was bubbled for 10min before heating the solution at 40° C. under a nitrogen atmosphere.After 1 h, Second Generation Grubbs Catalyst (201 mg, 0.237 mmol)dissolved in degassed DCM (20 ml) was added to the reaction mixturedropwise and heating continued at 40° C. overnight. The reaction mixturewas quenched with 1.5 M K₂HPO₃ (30 mL) followed by separation of theorganic phase and concentration. The crude residue was purified byreverse phase chromatography and concentration of product fractions. Theresidue was dissolved in MeOH, neutralized by passing through NaHCO₃resin cartridges (2×) and concentrating the filtrate to affordtert-butylN-[(11E,14S)-10-methyl-9-oxo-5,8,16-triazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,11,15,17-heptaen-14-yl]carbamate(24.6 mg, 6.59% yield) as brown film. MS(ESI) m/z: 395 (M+H)⁺.

265E. Preparation of tert-butylN-[(14S)-10-methyl-9-oxo-5,8,16-triazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-14-yl]carbamate

PtO₂ (0.018 g, 0.079 mmol) was added to a stirring solution oftert-butylN-[(11E,14S)-10-methyl-9-oxo-5,8,16-triazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,11,15,17-heptaen-14-yl]carbamate(0.031 g, 0.079 mmol) in EtOH (3 mL) and subjected to a H₂ atmosphere(55 psi) for 3 h. The catalyst was filtered off through a plug ofCELITE® and filtrate concentrated to give tert-butylN-[(14S)-10-methyl-9-oxo-5,8,16-triazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-14-yl]carbamateas a brown film (yield assumed quantitative). MS(ESI) m/z: 397 (M+H)⁺.

265F. Preparation of(14S)-14-amino-10-methyl-5,8,16-triazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-9-one

TFA (0.18 mL, 2.35 mmol) was added to a stirring solution of tert-butylN-[(14S)-10-methyl-9-oxo-5,8,16-triazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-14-yl]carbamate (31 mg, 0.078 mmol). After 6h, the reaction mixture was concentrated and the residue placed undervacuum overnight. The residue was dissolved in MeOH, passed a NaHCO₃resin cartridge, and concentrated to give(14S)-14-amino-10-methyl-5,8,16-triazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-9-oneas a brown film. The material was carried forward to the next reactionwithout further purification. MS(ESI) m/z: 297.3 (M+H)⁺.

265G. Preparation of(14S)-14-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-O-methyl-5,8,16-triazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-9-onetrifluoracetate

(14S)-14-(4-{5-Chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-10-methyl-5,8,16-triazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-9-one,trifluoroacetate was prepared (10.4 mg, 16.5%) in a similar manner asExample 56 using(14S)-14-amino-10-methyl-5,8,16-triazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-9-oneand6-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}pyrimidin-4-ol,prepared as described in Intermediate 15. The compound exists as anapparent diastereomeric mixture according to NMR data. MS(ESI) m/z:621.2 (M+H)⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.88-8.81 (m, 4H), 8.75-8.69 (m,3H), 8.07 (br. s., 1H), 8.03 (br. s., 1H), 7.96 (d, J=2.2 Hz, 1H),7.95-7.93 (m, 1H), 7.84-7.82 (m, 1H), 7.80-7.79 (m, 1H), 7.76-7.73 (m,2H), 7.59 (dd, J=5.0, 1.7 Hz, 1H), 7.47 (dd, J=5.1, 1.8 Hz, 1H), 7.27(s, 1H), 6.49-6.45 (m, 2H), 6.09 (dd, J=12.4, 4.7 Hz, 1H), 5.94-5.83 (m,2H), 4.61 (dd, J=15.2, 9.7 Hz, 1H), 2.94-2.86 (m, 1H), 2.79-2.70 (m,1H), 2.26 (s, 1H), 2.03 (d, J=13.0 Hz, 1H), 1.35-1.28 (m, 1H), 1.15 (d,J=6.6 Hz, 3H), 1.00 (d, J=6.8 Hz, 2H). Analytical HPLC (Method A):RT=5.22 min, purity=98%.

Example 267 Preparation of(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-9-methyl-4-(6-oxo-1,6-dihydropyridazin-4-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2,5,14,16-pentaen-8-one

(9R,13S)-13-(4-{5-Chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-9-methyl-4-(6-oxo-1,6-dihydropyridazin-4-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2,5,14,16-pentaen-8-onetrifluoroacetate (2.8 mg, 10% yield) was prepared in a similar manner asthe procedure described in Example 216, by using5-iodopyridazin-3(2H)-one (7.28 mg, 0.033 mmol) and(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(20.0 mg, 0.033 mmol), prepared as described in Example 196. ¹H NMR (500MHz, DMSO-d₆) δ 9.64 (s, 1H), 9.21 (s, 1H), 8.80 (s, 1H), 8.70 (s, 1H),8.65 (d, J=2.4 Hz, 1H), 8.59 (d, J=4.9 Hz, 1H), 7.96 (d, J=1.8 Hz, 1H),7.89 (s, 1H), 7.86-7.76 (m, 2H), 7.63 (d, J=5.2 Hz, 1H), 7.30-7.00 (m,1H), 6.48 (s, 1H), 6.00 (br. s., 1H), 2.78 (br. s., 1H), 2.24 (d, J=16.2Hz, 2H), 1.91-1.76 (m, 1H), 1.55 (br. s., 1H), 1.40 (br. s., 1H), 0.92(d, J=6.7 Hz, 3H), 0.48 (br. s., 1H). MS(ESI) m/z: 704.0 [M+H]⁺.Analytical HPLC (Method B): RT=1.735 min, purity=98.0%; Factor XIaKi=0.21 nM, Plasma Kallikrein Ki=9 nM.

Example 268 Preparation of(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-4-(6-methoxypyrazin-2-yl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2,5,14,16-pentaen-8-one

(9R,13S)-13-(4-{5-Chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-4-(6-methoxypyrazin-2-yl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2,5,14,16-pentaen-8-onetrifluoroacetate (10.9 mg, 16% yield) was prepared in a similar manneras the procedure described in Example 216, by using2-iodo-6-methoxypyrazine (19.35 mg, 0.082 mmol) and(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(50.0 mg, 0.082 mmol), prepared as described in Example 196. ¹H NMR (500MHz, DMSO-d₆) δ 9.54 (s, 1H), 9.19 (s, 1H), 8.78 (s, 1H), 8.73 (s, 1H),8.66 (s, 1H), 8.56 (d, J=4.9 Hz, 1H), 8.28 (s, 1H), 7.96-7.88 (m, 1H),7.84-7.75 (m, 2H), 7.61 (d, J=4.6 Hz, 1H), 7.21-6.93 (m, 1H), 6.46 (s,1H), 6.00 (br. s., 1H), 4.01 (s, 3H), 2.75 (br. s., 1H), 2.31-2.14 (m,2H), 1.85-1.73 (m, 1H), 1.53 (br. s., 1H), 1.37 (br. s., 1H), 0.90 (d,J=6.7 Hz, 3H), 0.52 (br. s., 1H). MS(ESI) m/z: 718.0 [M+H]⁺. AnalyticalHPLC (Method B): RT=2.06 min, purity=100.0%; Factor XIa Ki=9 nM, PlasmaKallikrein Ki=260 nM.

Example 269 Preparation of(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-4-(5-fluoro-2-methoxypyridin-4-yl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2,5,14,16-pentaen-8-one

(9R,13S)-13-(4-{5-Chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-4-(5-fluoro-2-methoxypyridin-4-yl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2,5,14,16-pentaen-8-one(6.6 mg, 19%) was prepared in a similar manner as the proceduredescribed in Example 216, by using 5-fluoro-4-iodo-2-methoxypyridine (21mg, 0.082 mmol) and(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(0.025 g, 0.041 mmol), prepared as described in Example 196. MS(ESI)m/z: 735.4 (M+H)⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 9.60 (s, 1H), 9.23 (s,1H), 8.72 (s, 1H), 8.60 (d, J=5.2 Hz, 1H), 8.49 (d, J=1.8 Hz, 1H), 8.43(d, J=3.1 Hz, 1H), 7.98 (d, J=2.1 Hz, 1H), 7.92 (s, 1H), 7.90-7.80 (m,2H), 7.64 (d, J=4.9 Hz, 1H), 7.39 (d, J=5.5 Hz, 1H), 6.51 (s, 1H),6.12-5.90 (m, 1H), 3.93 (s, 3H), 2.79 (br. s., 1H), 2.27 (d, J=17.7 Hz,2H), 1.84 (br. s., 1H), 1.57 (br. s., 1H), 1.49-1.34 (m, 1H), 0.94 (d,J=6.7 Hz, 3H), 0.68-0.41 (m, 1H). Analytical HPLC (Method C): RT=2.09min, purity=100%; Factor XIa Ki=7.4 nM, Plasma Kallikrein Ki=280 nM.

Example 270 Preparation of(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaene-17-carbonitrile

270A. Preparation of tert-butylN-[(9R,10E,13S)-17-cyano-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate

tert-ButylN-[(9R,10E,13S)-17-cyano-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate(0.02 g, 45%), a dark film, was prepared in the same manner as describedfor Intermediate 35D, substituting 2-bromo-4-formylbenzonitrile for3-bromobenzaldehyde. LCMS(ESI) m/z: 458.6 (M+H)⁺.

270B. Preparation of tert-butylN-[(9R,13S)-17-cyano-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate

tert-ButylN-[(9R,10E,13S)-17-cyano-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate(20 mg, 0.044 mmol) in EtOH (10 ml) was added PtO₂ (0.005 g, 0.022 mmol)and the reaction was hydrogenated at 55 psi for 5 h. The reactionmixture was filtered through a plug of CELITE® and the filtrateconcentrated. To the product was added DCM (2 ml), TEA (6.09 μl, 0.044mmol) and Dess-Martin periodinane (74.2 mg, 0.175 mmol). After 1 h atrt, the reaction was quenched with sat aq Na₂S₂O₃, and extracted withEtOAc (2×15 ml). The combined organic layer was washed with brine (10ml), dried (MgSO₄), filtered and concentrated to afford tert-butylN-[(9R,13S)-17-cyano-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate(20 mg 100%). MS(ESI) m/z: 460.5 (M+H)⁺.

270C. Preparation of(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaene-17-carbonitrile

To tert-butylN-[(9R,13S)-17-cyano-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate(20 mg, 0.044 mmol) was added dioxane (1 ml) followed by 1 ml of 4 N HClin dioxane. After 3 h, the reaction was concentrated and residuedissolved in DCM/MeOH and filtered through a basic cartridge.Concentration of the filtrate afforded(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaene-17-carbonitrile(12 mg, 80%) as a brown solid. MS(ESI) m/z: 360.4 (M+H)⁺.

270D. Preparation of(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaene-17-carbonitrile

(9R,13S)-13-(4-{5-Chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaene-17-carbonitrile(2.2 mg, 9.6%) was prepared in a similar manner as described in Example56 by using(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaene-17-carbonitrile.MS(ESI) m/z: 683.9 (M+H)⁺. ¹H NMR (500 MHz, CD₃OD) δ 8.71 (s, 1H), 8.13(s, 1H), 7.87 (d, J=8.0 Hz, 1H), 7.80 (m, 2H), 7.68-7.61 (m, 3H),7.58-7.51 (m, 2H), 6.34 (s, 1H), 5.62 (d, J=12.9 Hz, 1H), 2.45-2.34 (m,1H), 2.22 (br. s., 1H), 2.00 (d, J=16.2 Hz, 1H), 1.64 (d, J=10.2 Hz,2H), 1.44 (d, J=7.2 Hz, 1H), 1.06 (d, J=6.6 Hz, 3H), 0.62 (br. s., 1H).Analytical HPLC (Method C) RT=1.93 min, purity=100% as a mixture ofdiastereomers; Factor XIa Ki=0.35 nM, Plasma Kallikrein Ki=84 nM.

Example 271 Preparation of(9R,13S)-13-{4-[5-chloro-2-(4-methyl-1H-imidazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

(9R,13S)-13-{4-[5-Chloro-2-(4-methyl-1H-imidazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate (11.7 mg, 45% yield) was a major product isolated fromthe preparation of(9R,13S)-13-{4-[5-chloro-2-(5-methyl-1H-imidazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate, Example 257. MS(ESI) m/z: 569.20 (M+H)⁺. ¹H NMR (500MHz, DMSO-d₆) δ 9.23 (s, 1H), 9.14 (br. s., 1H), 8.77 (s, 1H), 8.68 (d,J=4.9 Hz, 1H), 7.94 (d, J=2.1 Hz, 1H), 7.85 (dd, J=8.4, 2.3 Hz, 1H),7.76 (d, J=8.5 Hz, 1H), 7.67 (s, 1H), 7.59 (d, J=5.2 Hz, 1H), 7.52-7.47(m, 2H), 6.60 (s, 1H), 5.90 (d, J=9.8 Hz, 1H), 4.01 (s, 3H), 2.69-2.61(m, 1H), 2.35-2.24 (m, 4H), 2.16-2.06 (m, 1H), 1.88-1.78 (m, 1H),1.52-1.42 (m, 1H), 1.38-1.28 (m, 1H), 0.89 (d, J=7.0 Hz, 3H), 0.53-0.38(m, 1H). Analytical HPLC (Method C): RT=1.14 min, 100% purity; FactorXIa Ki=90 nM, Plasma Kallikrein Ki=4,600 nM.

Example 272 Preparation of(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-4-(5-fluoro-2-hydroxypyridin-4-yl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2,5,14,16-pentaen-8-one

(9R,13S)-13-(4-{5-Chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-4-(5-fluoro-2-methoxypyridin-4-yl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2,5,14,16-pentaen-8-one,prepared as described in Example 269, (0.02 g, 0.027 mmol) was dissolvedin THF (2 mL) and conc. HCl (500 μl, 6.00 mmol) was added and thereaction mixture was heated to 70° C. for 16 h. After this time, thesolvents were concentrated and the residue was purified by reverse phasechromatography to give(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-4-(5-fluoro-2-hydroxypyridin-4-yl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2,5,14,16-pentaen-8-one(5.3 mg, 26%). MS(ESI) m/z: 721.2 (M+H)⁺. ¹H NMR (500 MHz, DMSO-d₆) δ9.59 (s, 1H), 9.24 (s, 1H), 8.73 (s, 1H), 8.60 (d, J=4.9 Hz, 1H), 8.43(s, 1H), 8.05 (br. s., 1H), 7.98 (d, J=1.8 Hz, 1H), 7.92 (s, 1H),7.90-7.79 (m, 2H), 7.63 (d, J=4.0 Hz, 1H), 6.96 (br. s., 1H), 6.51 (s,1H), 6.14-5.94 (m, 1H), 2.79 (br. s., 1H), 2.27 (d, J=17.1 Hz, 2H),1.91-1.77 (m, 1H), 1.64-1.50 (m, 1H), 1.49-1.34 (m, 1H), 0.94 (d, J=6.7Hz, 3H), 0.64-0.42 (m, 1H). Analytical HPLC (Method C): RT=1.68 min,purity=100%; Factor XIa Ki=0.73 nM, Plasma Kallikrein Ki=130 nM.

Example 274 Preparation of(9R,13S)-13-{4-[5-chloro-2-(1,3-oxazol-2-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

To a degassed dioxane (1 ml) solution of(9R,13S)-13-[4-(5-chloro-2-iodophenyl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(20 mg, 0.033 mmol), prepared as described in Example 211, was added2-(tributylstannyl)oxazole (11.65 mg, 0.033 mmol), followed by additionof Pd(Ph₃P)₄ (3.76 mg, 3.25 μmol). The reaction was stirred at 90° C.for 2 h, then cooled to rt and concentrated. Purification by reversephase chromatography afforded(9R,13S)-13-{4-[5-chloro-2-(1,3-oxazol-2-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate (2.38 mg, 11% yield) as a white solid. MS(ESI) m/z:556.4 (M+H)⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.89 (s, 1H), 8.74 (d, J=5.1 Hz,1H), 7.92 (d, J=8.4 Hz, 1H), 7.87 (s, 1H), 7.71 (s, 1H), 7.69 (d, J=2.2Hz, 1H), 7.65 (dd, J=8.4, 2.2 Hz, 1H), 7.52 (dd, J=5.1, 1.5 Hz, 1H),7.49 (s, 1H), 7.23 (s, 1H), 6.50 (s, 1H), 6.05 (dd, J=12.7, 4.1 Hz, 1H),4.05 (s, 3H), 2.77-2.67 (m, 1H), 2.38-2.27 (m, 1H), 2.15-1.98 (m, 2H),1.68-1.42 (m, 2H), 1.01 (d, J=7.0 Hz, 3H), 0.77-0.62 (m, 1H). AnalyticalHPLC (Method A): RT=7.13 min, 99.0% purity; Factor XIa Ki=100 nM, PlasmaKallikrein Ki=4,500 nM.

Example 275 Preparation of(9R,13S)-13-(4-{5-chloro-2-[(pyrazin-2-yl)amino]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

A sealed microwave vial containing(9R,13S)-13-[4-(2-amino-5-chlorophenyl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onehydrochloride (0.01 g, 0.017 mmol), prepared as described in Example313, 2-bromopyrazine (5.51 mg, 0.035 mmol) and EtOH (1 ml) was heated ina microwave at 150° C. for 30 min, cooled to rt, and concentrated. Tothe residue were added Cs₂CO₃ (0.030 g, 0.093 mmol), Pd(OAc)₂ (1.05 mg,4.66 μmol), Xantphos (5.39 mg, 9.31 μmol), and 2-bromopyrazine (5.51 mg,0.035 mmol), followed by dioxane (0.931 ml). The reaction mixture wasdegassed with Ar for 10 min. The vial was sealed and heated at 85° C.After 4 h, the reaction was cooled to rt and concentrated. Purificationby reverse phase chromatography afforded(9R,13S)-13-(4-{5-chloro-2-[(pyrazin-2-yl)amino]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate (2.95 mg, 20% yield) as a yellow solid. MS(ESI) m/z:582.5 (M+H)⁺. ¹H NMR (400 MHz, CD₃OD) δ 9.09 (s, 1H), 8.73 (d, J=5.1 Hz,1H), 8.23-8.19 (m, 2H), 8.08 (dd, J=2.8, 1.4 Hz, 1H), 7.89 (d, J=2.6 Hz,1H), 7.73 (s, 1H), 7.67 (d, J=2.6 Hz, 1H), 7.53 (dd, J=5.1, 1.5 Hz, 1H),7.50 (s, 1H), 7.43 (dd, J=8.9, 2.5 Hz, 1H), 6.77 (s, 1H), 6.02 (dd,J=12.7, 4.3 Hz, 1H), 4.05 (s, 3H), 2.76-2.67 (m, 1H), 2.43-2.32 (m, 1H),2.15-2.01 (m, 2H), 1.68-1.44 (m, 2H), 1.02 (d, J=6.8 Hz, 3H), 0.81-0.65(m, 1H). Analytical HPLC (Method A): RT=7.06 min, 94.0% purity; FactorXIa Ki=560 nM.

Example 276 Preparation of(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-4-(4-hydroxypyrimidin-5-yl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2,5,14,16-pentaen-8-one

(9R,13S)-13-(4-{5-Chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-4-(4-hydroxypyrimidin-5-yl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2,5,14,16-pentaen-8-onetrifluoroacetate was prepared in a similar manner as the proceduredescribed in Example 296, to give

(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-4-(4-hydroxypyrimidin-5-yl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2,5,14,16-pentaen-8-onetrifluoroacetate (3.82 mg, 4.44 μmol, 42% yield). ¹H NMR (400 MHz,CD₃OD) δ 8.85 (s, 1H), 8.75 (s, 2H), 8.71 (s, 1H), 8.67-8.62 (m, 1H),8.27 (s, 1H), 8.00-7.93 (m, 2H), 7.82-7.69 (m, 3H), 6.49 (s, 1H), 6.13(d, J=9.2 Hz, 1H), 2.87 (br. s., 1H), 2.29 (br. s., 2H), 2.13-2.01 (m,1H), 1.76 (d, J=10.3 Hz, 1H), 1.59 (br. s., 1H), 1.29 (s, 1H), 1.11 (d,J=7.0 Hz, 3H), 0.91 (br. s., 1H). MS(ESI) m/z: 704.5 [M+H]+. AnalyticalHPLC (Method A): RT=7.04 min, purity=>95.0%; Factor XIa Ki=2.4 nM,Plasma Kallikrein Ki=70 nM.

Example 277 Preparation of ethyl1-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)-3-methyl-1H-pyrazole-4-carboxylate

To a suspension of ethyl 3-methyl-1H-pyrazole-4-carboxylate (3.51 mg,0.023 mmol), K₃PO₄ (9.79 mg, 0.046 mmol) and(9R,13S)-13-[4-(5-chloro-2-iodophenyl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(14 mg, 0.023 mmol) in dioxane (0.24 mL) was added(1R,2R)—N1,N2-dimethylcyclohexane-1,2-diamine (1.619 mg, 0.011 mmol).The mixture was purged with Ar, CuI (0.434 mg, 2.277 μmol) was added,and the vial was sealed. The reaction was heated at 80° C. and stirredovernight. The solution was concentrated and the residue purified byreverse phase chromatography to give ethyl1-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)-3-methyl-1H-pyrazole-4-carboxylatetrifluoroacetate (3.21 mg, 17% yield) as a white solid. MS(ESI) m/z:641.2 (M+H)⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.86 (s, 1H), 8.71 (d, J=5.1 Hz,1H), 8.20 (s, 1H), 7.84 (d, J=2.2 Hz, 1H), 7.68 (s, 1H), 7.67-7.61 (m,1H), 7.60-7.54 (m, 1H), 7.53-7.47 (m, 2H), 6.20 (s, 1H), 6.02-5.95 (m,1H), 4.30-4.21 (m, 2H), 4.07-4.01 (m, 3H), 2.70 (td, J=6.7, 3.2 Hz, 1H),2.36 (s, 3H), 2.33-2.24 (m, 1H), 2.13-1.95 (m, 2H), 1.65-1.53 (m, 1H),1.51-1.40 (m, 1H), 1.34-1.26 (m, 3H), 1.00 (d, J=7.0 Hz, 3H), 0.69 (m,1H). Analytical HPLC (Method A): RT=7.46 min, 94% purity; Factor XIaKi=170 nM, Plasma Kallikrein Ki=2,700 nM.

Example 278 Preparation of(9R,13S)-13-{4-[5-chloro-2-(3,4-dimethyl-1H-pyrazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

(9R,13S)-13-{4-[5-Chloro-2-(3,4-dimethyl-1H-pyrazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate (0.85 mg, 5% yield) was prepared in a similar manner asthe procedure described in Example 277, by replacing ethyl3-methyl-1H-pyrazole-4-carboxylate with 3,4-dimethyl-1H-pyrazole (2.189mg, 0.023 mmol). MS(ESI) m/z: 583.2 (M+H)⁺. ¹H NMR (400 MHz, CD₃OD) δ8.91 (s, 1H), 8.72 (d, J=5.1 Hz, 1H), 7.86 (d, J=2.4 Hz, 1H), 7.68 (s,1H), 7.60 (dd, J=8.6, 2.4 Hz, 1H), 7.51 (dd, J=5.1, 1.5 Hz, 1H),7.49-7.46 (m, 2H), 7.39 (s, 1H), 6.02-5.94 (m, 2H), 4.04 (s, 3H), 2.71(d, J=3.1 Hz, 1H), 2.37-2.24 (m, 1H), 2.14 (s, 3H), 2.00 (s, 3H), 1.93(s, 1H), 1.66-1.54 (m, 1H), 1.48 (m, 1H), 1.01 (d, J=6.8 Hz, 3H), 0.68(m, 1H). Analytical HPLC (Method A): RT=6.78 min, 92% purity; Factor XIaKi=540 nM.

Example 279 Preparation of ethyl1-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)-1H-pyrazole-4-carboxylate

Ethyl1-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)-1H-pyrazole-4-carboxylatetrifluoroacetate (9.9 mg, 56% yield) was prepared in a similar manner asthe procedure described in Example 277, by replacing ethyl3-methyl-1H-pyrazole-4-carboxylate with ethyl 1H-pyrazole-4-carboxylate(3.19 mg, 0.023 mmol). MS(ESI) m/z: 627.1 (M+H)⁺. ¹H NMR (400 MHz,methanol-d4) δ 8.86 (s, 1H), 8.72 (d, J=5.3 Hz, 1H), 8.34 (s, 1H), 7.96(s, 1H), 7.85 (d, J=2.2 Hz, 1H), 7.69 (s, 1H), 7.68-7.64 (m, 1H),7.61-7.57 (m, 1H), 7.53 (dd, J=5.2, 1.7 Hz, 1H), 7.49 (s, 1H), 6.18 (s,1H), 5.98 (dd, J=12.7, 4.3 Hz, 1H), 4.28 (q, J=7.1 Hz, 2H), 4.04 (s,3H), 2.70 (td, J=6.7, 3.3 Hz, 1H), 2.30 (tt, J=12.7, 4.4 Hz, 1H),2.12-1.94 (m, 2H), 1.66-1.53 (m, 1H), 1.46 (ddd, J=15.0, 9.8, 5.5 Hz,1H), 1.32 (t, J=7.2 Hz, 3H), 1.00 (d, J=6.8 Hz, 3H), 0.69 (m, 1H).Analytical HPLC (Method A): RT=7.06 min, 99% purity; Factor XIa Ki=2.2nM, Plasma Kallikrein Ki=960 nM.

Example 280 Preparation of(9R,13S)-13-[4-(5-chloro-2-hydroxyphenyl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

The mixture of 1H-imidazole (2.21 mg, 0.033 mmol), Pd(OAc)₂ (0.73 mg,3.25 mol) and CuI (0.012 g, 0.065 mmol) in DMF (1.63 ml) was purged withAr (3×), and then(9R,13S)-13-[4-(5-chloro-2-iodophenyl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(0.02 g, 0.033 mmol), prepared as described in Example 211, was added.The reaction was sealed and heated at 140° C. After 5 h, the reactionwas cooled to rt. The solution was concentrated and the residue waspurified by reverse phase chromatography afforded(9R,13S)-13-[4-(5-chloro-2-hydroxyphenyl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate (1.76 mg, 9% yield) as a yellow solid. MS(ESI) m/z:505.6 (M+H)⁺. ¹H NMR (400 MHz, CD₃OD) δ 9.11 (s, 1H), 8.74 (d, J=5.1 Hz,1H), 7.84 (d, J=2.6 Hz, 1H), 7.72 (s, 1H), 7.52 (dd, J=5.1, 1.5 Hz, 1H),7.50 (s, 1H), 7.30 (dd, J=8.8, 2.6 Hz, 1H), 7.07 (s, 1H), 6.90 (d, J=8.8Hz, 1H), 6.06 (dd, J=12.9, 4.5 Hz, 1H), 4.05 (s, 3H), 2.78-2.68 (m, 1H),2.35 (tt, J=12.8, 4.3 Hz, 1H), 2.16-2.01 (m, 2H), 1.68-1.45 (m, 2H),1.01 (d, J=7.0 Hz, 3H), 0.76-0.61 (m, 1H). Analytical HPLC (Method A):RT=8.47 min, 100% purity; Factor XIa Ki=57 nM, Plasma Kallikrein Ki=180nM.

Example 281 Preparation of(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-imidazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

(9R,13S)-13-(4-{5-Chloro-2-[4-(trifluoromethyl)-1H-imidazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate (4 mg, 15% yield) was prepared in a similar manner asthe procedure described in Example 231, by replacing 1H-imidazole with4-(trifluoromethyl)-1H-imidazole (0.018 g, 0.130 mmol). MS(ESI) m/z:623.25 (M+H)⁺. ¹H NMR (500 MHz, CD₃OD) δ 8.84 (s, 1H), 8.70 (d, J=5.2Hz, 1H), 7.86 (s, 1H), 7.83 (d, J=2.5 Hz, 1H), 7.74 (s, 1H), 7.71-7.66(m, 2H), 7.58 (d, J=8.5 Hz, 1H), 7.52-7.47 (m, 2H), 6.40 (s, 1H), 5.99(dd, J=12.5, 3.4 Hz, 1H), 4.04 (s, 3H), 2.70 (dt, J=6.6, 3.3 Hz, 1H),2.33-2.23 (m, 1H), 2.12-1.92 (m, 2H), 1.65-1.55 (m, 1H), 1.52-1.41 (m,1H), 1.01 (d, J=6.9 Hz, 3H), 0.76-0.60 (m, 1H). Analytical HPLC (MethodC): RT=1.58 min, 100% purity; Factor XIa Ki=73 nM, Plasma KallikreinK_(i)=4,700 nM.

Example 282 Preparation of(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-4-methanesulfonyl-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2,5,14,16-pentaen-8-one,and Preparation of(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-methanesulfonyl-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

To a cooled (0° C.), clear, pale pink solution of(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate (0.010 g, 0.014 mmol), prepared as described in Example101, and pyridine (0.012 ml, 0.145 mmol) was added MsCl (1.1 μl, 0.014mmol). The reaction was stirred for 30 min at 0° C. and then thereaction was warmed to rt. After 1 h at rt, TEA (0.020 ml, 0.145 mmol)was added followed by MsCl (1.1 μl, 0.014 mmol). After 3 h, additionalTEA (0.020 ml, 0.145 mmol) was added followed by the additional of MsCl(5.5 μL, 0.070 mmol). After 1 h, the reaction was stopped, diluted withEtOAc and washed with 1.5 M K₂HPO₄, brine, dried over Na₂SO₄, filteredand concentrated to give a yellow residue. Purification by reverse phasechromatography, gave after concentration and lyophilization a 1:1mixture of(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-4-methanesulfonyl-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2,5,14,16-pentaen-8-onetrifluoroacetate and(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-methanesulfonyl-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate (0.0020 g, 18%) as a white solid. MS(ESI) m/z: 654.0(M+H)⁺. ¹H NMR (500 MHz, CD₃OD) δ 8.87 (s, 1H), 8.79 (s, 1H), 8.67 (d,J=5.2 Hz, 2H), 8.34-8.32 (m, 2H), 8.28 (s, 1H), 7.90-7.87 (m, 4H),7.75-7.71 (m, 2H), 7.66-7.63 (m, 3H), 7.62-7.60 (m, 1H), 7.55 (dd,J=5.2, 1.7 Hz, 1H), 6.38-6.36 (m, 2H), 6.13-6.06 (m, 1H), 5.99-5.93 (m,1H), 3.52 (s, 3H), 3.49 (s, 3H), 2.86-2.79 (m, 1H), 2.68-2.61 (m, 1H),2.32-2.20 (m, 3H), 2.07-1.90 (m, 3H), 1.76-1.64 (m, 1H), 1.62-1.38 (m,3H), 1.04 (d, J=6.9 Hz, 3H), 0.98 (d, J=6.9 Hz, 3H), 0.80-0.61 (m, 2H).Analytical HPLC (Method A): RT=7.98 and 8.11 min, purity=96.9%; FactorXIa Ki=1.2 nM, Plasma Kallikrein Ki=290 nM.

Example 283 Preparation of(9R,13S)-13-(4-{2,3-difluoro-6-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

(9R,13S)-13-(4-{2,3-Difluoro-6-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(12 mg, 100% yield) as a solid was prepared via the coupling of6-{2,3-difluoro-6-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}pyrimidin-4-ol(0.007 g, 0.02 mmol) and(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one (0.07 g, 0.02 mmol) using the HATU, DBU couplingmethodology as described in Example 56. MS m/z=662.1 (M+H)⁺. ¹H NMR (500MHz, DMSO-d₆) δ9.34-9.30 (m, 1H), 9.15-9.11 (m, 1H), 8.74-8.71 (m, 1H),8.63-8.59 (m, 1H), 7.85-7.79 (m, 2H), 7.72-7.67 (m, 1H), 7.64-7.61 (m,1H), 7.38-7.35 (m, 1H), 6.62-6.58 (m, 1H), 5.88-5.73 (m, 1H), 2.63-2.50(m, 1H), 2.24-2.10 (m, 1H), 2.02-1.92 (m, 1H), 1.83-1.69 (m, 1H),1.46-1.16 (m, 2H), 0.84-0.70 (d, 3H), 0.37-0.17 (m, 1H). Analytical HPLC(Method B) RT=1.73 min, purity=99%; Factor XIa Ki=2 nM, PlasmaKallikrein Ki=570 nM.

Example 284 Preparation of methyl1-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)-1H-imidazole-4-carboxylate

Methyl1-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)-1H-imidazole-4-carboxylatetrifluoroacetate (10 mg, 24% yield) was prepared in a similar manner asthe procedure described in Example 231, by replacing 1H-imidazole with1H-imidazole-4-carboxylate hydrochloride (0.025 g, 0.195 mmol). MS(ESI)m/z: 613.5 (M+H)⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.80 (s, 1H), 8.68 (d,J=5.3 Hz, 1H), 8.29 (s, 1H), 8.06 (s, 1H), 7.87 (d, J=2.2 Hz, 1H), 7.72(dd, J=8.6, 2.4 Hz, 1H), 7.68 (s, 1H), 7.62 (d, J=8.4 Hz, 1H), 7.51 (dd,J=5.1, 1.5 Hz, 1H), 7.49 (s, 1H), 6.47 (s, 1H), 5.96 (dd, J=12.4, 3.9Hz, 1H), 4.04 (s, 3H), 3.87 (s, 3H), 2.75-2.65 (m, 1H), 2.33-2.22 (m,1H), 2.11-1.92 (m, 2H), 1.64-1.39 (m, 2H), 1.00 (d, J=6.8 Hz, 3H), 0.67(br. s., 1H). Analytical HPLC (Method A): RT=6.10 min, 99.9% purity;Factor XIa Ki=16 nM, Plasma Kallikrein Ki=1,800 nM.

Example 285 Preparation of(9R,13S)-13-[4-(2,5-dichlorophenyl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

(9R,13S)-13-[4-(2,5-Dichlorophenyl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate (4.3 mg, 13% yield) was a minor product isolated fromthe preparation of methyl1-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)-1H-imidazole-4-carboxylate,Example 284. MS(ESI) m/z: 523.5 (M+H)⁺. ¹H NMR (400 MHz, CD₃OD) δ 9.04(s, 1H), 8.74 (d, J=5.3 Hz, 1H), 7.73 (s, 1H), 7.68 (d, J=2.4 Hz, 1H),7.55-7.49 (m, 3H), 7.49-7.44 (m, 1H), 6.77 (d, J=0.7 Hz, 1H), 6.06 (dd,J=12.7, 4.1 Hz, 1H), 4.05 (s, 3H), 2.78-2.68 (m, 1H), 2.38 (tt, J=12.8,4.3 Hz, 1H), 2.16-2.02 (m, 2H), 1.68-1.45 (m, 2H), 1.02 (d, J=6.8 Hz,3H), 0.70 (br. s., 1H). Analytical HPLC (Method A): RT=8.29 min, 98.6%purity; Factor XIa Ki=50 nM, Plasma Kallikrein Ki=770 nM.

Example 286 Preparation of(9R,13R)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,18-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate

286A. Preparation of(9R,13R)-13-amino-3,9-dimethyl-3,4,7,18-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

(9R,13R)-13-Amino-3,9-dimethyl-3,4,7,18-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(15 mg, 100% yield) was prepared in a similar manner as the proceduresdescribed in Intermediate 28, by replacing(S)-2-methyl-N-[(1S)-1-[6-(1-methyl-4-nitro-1H-pyrazol-5-yl)pyridin-2-yl]but-3-en-1-yl]propane-2-sulfinamide(Diastereomer B) with(S)-2-methyl-N-[(1R)-1-[6-(1-methyl-4-nitro-1H-pyrazol-5-yl)pyridin-2-yl]but-3-en-1-yl]propane-2-sulfinamide(Diastereomer A). MS(ESI) m/z: 300.5 (M+H)⁺.

286B. Preparation of(9R,13R)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,18-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate

(9R,13R)-13-{4-[5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,18-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate (7.2 mg, 19% yield) was prepared in a similar manner asthe procedure described in Example 56, by using6-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol(15.4 mg, 0.050 mmol) and(9R,13R)-13-amino-3,9-dimethyl-3,4,7,18-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one,(15 mg, 0.050 mmol), prepared as described in Example 286A. MS(ESI) m/z:590.25 (M+H)⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 9.47 (s, 1H), 8.72 (s, 1H),8.66 (s, 1H), 7.94 (t, J=7.9 Hz, 1H), 7.90 (d, J=2.4 Hz, 1H), 7.85-7.79(m, 1H), 7.77-7.70 (m, 2H), 7.52 (s, 1H), 7.23 (d, J=7.6 Hz, 1H), 6.48(s, 1H), 5.89 (dd, J=12.4, 2.9 Hz, 1H), 4.10 (s, 3H), 3.91 (s, 1H),3.08-2.94 (m, 1H), 2.74 (dt, J=11.4, 5.8 Hz, 1H), 1.70-1.57 (m, 1H),1.50-1.29 (m, 3H), 1.05 (d, J=6.7 Hz, 3H), 0.98 (m, 1H). Analytical HPLC(Method B): RT 1.64 min, purity=95%; Factor XIa Ki=1,800 nM.

Example 287 Preparation of(9R,13S)-13-(4-{2,3-difluoro-6-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(²H₃)methyl-9-methyl-3,4,7,17-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

(9R,13S)-13-(4-{2,3-Difluoro-6-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(²H₃)methyl-9-methyl-3,4,7,17-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(3 mg, 27% yield) as a solid was prepared via the coupling of6-{2,3-difluoro-6-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}pyrimidin-4-ol(0.005 g, 0.015 mmol) and(9R,13S)-13-amino-3-(²H₃)methyl-9-methyl-3,4,7,17-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(0.004 g, 0.015 mmol) using the HATU, DBU coupling methodology asdescribed in Example 56. MS m/z=629.1 (M+H)⁺. ¹H NMR (500 MHz, DMSO-d₆)δ 9.30-9.26 (m, 1H), 9.23-9.17 (m, 1H), 8.67-8.61 (m, 1H), 8.58-8.53 (m,1H), 7.96-7.86 (m, 1H), 7.81-7.74 (m, 2H), 7.45 (s, 1H), 6.98-6.94 (m,1H), 6.73-6.69 (m, 1H), 5.65-5.48 (m, 1H), 2.55 (s, 1H), 2.44-2.28 (m,1H), 2.03-1.81 (m, 2H), 1.99-1.76 (m, 2H), 1.53-1.38 (m, 2H), 1.32-1.19(m, 1H), 1.15-1.06 (d, 3H), 1.01-0.91 (m, 1H). Analytical HPLC (MethodB) RT=1.55 min, purity=94%; Factor XIa Ki=4 nM, Plasma Kallikrein Ki=520nM.

Example 288 Preparation of1-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)-1H-imidazole-4-carboxylicacid

To the solution of methyl1-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)-1H-imidazole-4-carboxylate(0.008 g, 9.51 μmol), prepared as described in Example 284, in MeOH (1ml) was added 1 N NaOH (0.057 ml, 0.057 mmol). After stirring at rt for24 h, the reaction was quenched with a few drops of TFA. Purification byreverse phase chromatography afforded1-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)-1H-imidazole-4-carboxylicacid trifluoroacetate (4.8 mg, 61% yield) as a white solid. MS(ESI) m/z:599.5 (M+H)⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.76 (s, 1H), 8.71-8.66 (m, 2H),8.11 (br. s., 1H), 7.89 (d, J=2.2 Hz, 1H), 7.77-7.72 (m, 1H), 7.70-7.65(m, 2H), 7.51-7.48 (m, 2H), 6.58 (s, 1H), 5.97 (dd, J=12.5, 4.2 Hz, 1H),4.04 (s, 3H), 2.75-2.64 (m, 1H), 2.34-2.22 (m, 1H), 2.12-1.93 (m, 2H),1.65-1.39 (m, 2H), 1.00 (d, J=6.8 Hz, 3H), 0.79-0.62 (m, 1H). AnalyticalHPLC (Method A): RT=5.13 min, 99.5% purity; Factor XIa Ki=3.7 nM, PlasmaKallikrein Ki=450 nM.

Example 289 Preparation of(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,18-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

(9R,13S)-13-{4-[5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,18-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate (1.8 mg, 50% yield) was prepared in a similar manner asthe procedure described in Example 56, by using6-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol(15.4 mg, 0.050 mmol) and(9R,13S)-13-amino-3,9-dimethyl-3,4,7,18-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one,15 mg, 0.050 mmol), prepared as described in Intermediate 28. MS(ESI)m/z: 590.25 (M+H)⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 9.41 (s, 1H), 8.71 (s,1H), 8.15 (s, 1H), 7.97 (t, J=7.8 Hz, 1H), 7.90 (d, J=2.4 Hz, 1H),7.84-7.79 (m, 1H), 7.75 (dd, J=8.1, 6.0 Hz, 2H), 7.52 (s, 1H), 7.20 (d,J=7.9 Hz, 1H), 6.48 (s, 1H), 5.97 (d, J=8.5 Hz, 1H), 4.04 (s, 3H), 3.91(s, 1H), 2.58 (m, 1H), 2.44-2.31 (m, 1H), 2.09 (d, J=7.6 Hz, 1H),1.83-1.73 (m, 1H), 1.53-1.39 (m, 2H), 1.23 (m, 1H), 1.00 (d, J=6.7 Hz,3H). Analytical HPLC (Method B): RT 1.59 min, purity=93%; Factor XIaKi=2.3 nM, Plasma Kallikrein Ki=380 nM.

Example 290 Preparation of(10R,14S)-14-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-10-methyl-3,5,8-triazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-9-one

(10R,14S)-14-{4-[5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-10-methyl-3,5,8-triazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-9-onetrifluoroacetate (0.004 g, 28%) was prepared according to the proceduresdescribed in Example 206 by using(10R,14S)-14-amino-10-methyl-3,5,8-triazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2,4,6,15,17-hexaen-9-one,prepared as described in Intermediate 38, and 4-bromopyrimidin-5-aminein prepared as described in Intermediate 38B. MS(ESI) m/z: 587.1 (M+H)⁺.¹H NMR (400 MHz, CD₃OD) δ 9.18 (s, 1H), 8.71 (s, 1H), 8.35-8.31 (m, 2H),8.01 (s, 1H), 7.87 (d, J=2.4 Hz, 1H), 7.86-7.83 (m, 1H), 7.76-7.71 (m,1H), 7.67-7.62 (m, 2H), 7.35 (d, J=7.9 Hz, 1H), 6.42 (d, J=0.7 Hz, 1H),5.84 (dd, J=13.0, 3.7 Hz, 1H), 2.72-2.59 (m, 1H), 2.40-2.27 (m, 1H),2.18-2.07 (m, 1H), 2.03-1.94 (m, 1H), 1.68-1.56 (m, 1H), 1.46-1.33 (m,2H), 1.15 (d, J=7.0 Hz, 3H). Analytical HPLC (Method A): RT=8.12 min,purity>99%; Factor XIa Ki=2.4 nM, Plasma Kallikrein Ki=150 nM.

Example 292 Preparation of(9R,13S)-13-{4-[5-chloro-1-(2-hydroxyethyl)-1H-indazol-7-yl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

292A and 292B. Preparation of7-bromo-5-chloro-1-(2-methoxyethyl)-1H-indazole, and7-bromo-5-chloro-2-(2-methoxyethyl)-2H-indazole

To a suspension of 7-bromo-5-chloro-1H-indazole (2.0 g, 8.64 mmol) andK₂CO₃ (5.97 g, 43.2 mmol) in DMSO (9.97 mL) was added1-bromo-2-methoxyethane (0.812 mL, 8.64 mmol) at rt under a blanket ofAr. After 14 h, the reaction mixture was diluted with water, extractedwith EtOAc. The combined organic layer was washed with water, brine,dried over Na₂SO₄, filtered, and concentrated. The crude mixture ofregioisomers (1:1) was purified by normal phase chromatography usinghexanes and EtOAc as eluants to afford7-bromo-5-chloro-1-(2-methoxyethyl)-1H-indazole as the early elutingisomer (less polar) (0.766 g, 30%) and7-bromo-5-chloro-2-(2-methoxyethyl)-2H-indazole as the late elutingisomer (more polar) (1.18 g, 47%).

292A. MS(ESI) m/z: 290 (M+H)⁺ and 292 (M+2+H)⁺. ¹H NMR (500 MHz, CDCl₃)δ 7.97 (s, 1H), 7.66 (d, J=1.7 Hz, 1H), 7.56 (d, J=1.9 Hz, 1H), 4.98 (t,J=6.1 Hz, 2H), 3.85 (t, J=6.1 Hz, 2H), 3.34 (s, 3H).

292B. MS(ESI) m/z: 290 (M+H)⁺ and 292 (M+2+H)⁺. ¹H NMR (400 MHz, CDCl₃)δ 8.08 (s, 1H), 7.60 (d, J=1.5 Hz, 1H), 7.48 (d, J=1.8 Hz, 1H),4.64-4.59 (m, 2H), 3.89-3.84 (m, 2H), 3.34 (s, 3H).

292C. Preparation of5-chloro-1-(2-methoxyethyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole

To a stirring solution of7-bromo-5-chloro-1-(2-methoxyethyl)-1H-indazole (0.766 g, 2.65 mmol) indioxane (13.23 mL) at RT was added4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (0.773 g,3.04 mmol) and KOAc (1.194 g, 12.17 mmol) and the system was purged withAr (3×). Pd(dppf)Cl₂CH₂Cl₁₂ complex (0.173 g, 0.212 mmol) was added, thereaction was purged with Ar, and heated to 90° C.

After stirring overnight, the reaction mixture was cooled to rt, dilutedwith water, extracted with EtOAc (3×). The combined organic layer waswashed with water, brine, dried over Na₂SO₄, filtered, and concentrated.MS(ESI) m/z: 337 (M+H)⁺.

292D. Preparation of5-chloro-1-(2-methoxyethyl)-7-(6-methoxypyrimidin-4-yl)-1H-indazole

4-Chloro-6-methoxypyrimidine (0.574 g, 3.97 mmol),5-chloro-1-(2-methoxyethyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole(0.891 g, 2.65 mmol) and 2 M aq Na₂CO₃ (2.65 mL, 5.29 mmol) were addedto DME (17.65 mL)/EtOH (2.206 mL) and purged with Ar for several min.Pd(dppf).CH₂Cl₂ Adduct (0.216 g, 0.265 mmol) was added and the reactionheated at 90° C. After 14 h, the reaction was diluted with water,extracted with EtOAc, the organic layer washed with brine, dried overNa₂SO₄, filtered, and concentrated to give a brown oil. The crudematerial was purified by normal phase chromatography using hexanes andEtOAc as eluents to give5-chloro-1-(2-methoxyethyl)-7-(6-methoxypyrimidin-4-yl)-1H-indazole(0.777 g, 92% yield) brown oil. MS(ESI) m/z: 319 (M+H)⁺.

292E. Preparation of6-(5-chloro-1-(2-hydroxyethyl)-1H-indazol-7-yl)pyrimidin-4-oltrifluoroacetate

To a suspension of5-chloro-1-(2-methoxyethyl)-7-(6-methoxypyrimidin-4-yl)-1H-indazole(0.300 g, 0.941 mmol) in ACN (3.14 mL) was added TMSI (1 mL, 7.35 mmol)at rt. Then, the clear yellow solution was heated to 50° C. After 4 h,the reaction mixture was cooled to rt, concentrated and purified byreverse phase chromatography (PHENOMENEX® Luna Axia C18 5μ 30×100 mmcolumn, 10-minute gradient; Solvent A: 30% MeOH—70% H₂O— 0.1% TFA;Solvent B: 90% MeOH—10% H₂O— 0.1% TFA) to give6-(5-chloro-1-(2-hydroxyethyl)-1H-indazol-7-yl)pyrimidin-4-oltrifluoroacetate (0.127 g, 33.3% yield) as a yellow solid. MS(ESI) m/z:291 (M+H)⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.52 (d, J=0.9 Hz, 1H), 8.17 (s,1H), 7.95 (d, J=2.0 Hz, 1H), 7.47 (d, J=2.0 Hz, 1H), 6.79 (d, J=0.9 Hz,1H), 4.45 (t, J=5.9 Hz, 2H), 3.80 (t, J=5.9 Hz, 2H).

292F. Preparation of(9R,13S)-13-{4-[5-chloro-1-(2-hydroxyethyl)-1H-indazol-7-yl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate

(9R,13S)-13-{4-[5-Chloro-1-(2-hydroxyethyl)-1H-indazol-7-yl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate (6.6 mg, 29%) was prepared in a similar manner asExample 56 using6-(5-chloro-1-(2-hydroxyethyl)-1H-indazol-7-yl)pyrimidin-4-oltrifluoroacetate and(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one,prepared as described in Intermediate 30. MS(ESI) m/z: 609 (M+H)⁺. ¹HNMR (400 MHz, DMSO-d₆) δ 9.36 (s, 1H), 9.02 (s, 1H), 8.70 (d, J=5.1 Hz,1H), 8.13 (s, 1H), 7.93 (d, J=2.0 Hz, 1H), 7.85 (s, 1H), 7.69 (s, 1H),7.40-7.35 (m, 2H), 6.68 (s, 1H), 5.93 (d, J=8.6 Hz, 1H), 4.40-4.28 (m,2H), 3.50-3.39 (m, 2H), 2.64-2.58 (m, 1H), 2.38-2.30 (m, 1H), 2.11-1.99(m, 1H), 1.96-1.85 (m, 1H), 1.50-1.39 (m, 1H), 1.36-1.27 (m, 1H), 0.83(d, J=7.0 Hz, 3H), 0.38-0.28 (m, 1H). Analytical HPLC (Method A):RT=7.16 min, purity=>95%; Factor XIa Ki=180 nM.

Example 293 Preparation of(9R,13S)-13-[4-(5-chloro-1-methyl-1H-indol-7-yl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

293A. Preparation of5-chloro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole

To a solution of 7-bromo-5-chloro-1H-indole (0.470 g, 2.039 mmol) indioxane (10.20 mL) at rt was added4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (0.595 g,2.345 mmol) and KOAc (0.921 g, 9.38 mmol), and the system was purgedwith Ar (3×). Pd(dppf)Cl₂.CH₂Cl₂ complex (0.133 g, 0.163 mmol) was addedand the reaction mixture was again purged with Ar, and heated to 90° C.After stirring overnight, the reaction mixture was cooled to rt, dilutedwith water, extracted with EtOAc (3×), organics washed with water,brine, dried over Na₂SO₄, filtered, and concentrated and the crudematerial was carried forward to the next reaction. MS(ESI) m/z: 278(M+H)⁺.

293B. Preparation of 5-chloro-7-(6-methoxypyrimidin-4-yl)-1H-indole

4-Chloro-6-methoxypyrimidine (0.391 g, 2.70 mmol),5-chloro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole(0.500 g, 1.801 mmol) and 2 M aq Na₂CO₃ (1.801 ml, 3.60 mmol) were addedto DME (14.41 mL)/EtOH (1.801 mL) and purged with Ar for several min.PdCl₂(dppf)-CH₂Cl₂ Adduct (0.147 g, 0.180 mmol) was added and heated at90° C. After 2 h, the reaction was diluted with water and extracted withEtOAc. The organic layer was washed with brine, dried over Na₂SO₄,filtered, and concentrated. The crude material was purified by normalphase chromatography using hexanes and EtOAc as eluants to give5-chloro-7-(6-methoxypyrimidin-4-yl)-1H-indole (0.339 g, 72.5% yield) asan amber solid. MS(ESI) m/z: 260 (M+H)⁺. ¹H NMR (400 MHz, CDCl₃) δ 11.21(br. s., 1H), 11.36-11.06 (m, 1H), 8.91 (d, J=1.1 Hz, 1H), 7.77-7.74 (m,1H), 7.72 (d, J=1.8 Hz, 1H), 7.40-7.38 (m, 1H), 7.30 (d, J=1.1 Hz, 1H),6.56 (dd, J=3.1, 2.4 Hz, 1H), 4.07 (s, 2H).

293C. Preparation of 6-(5-chloro-1-methyl-1H-indol-7-yl)pyrimidin-4-ol

MeI (0.212 ml, 3.39 mmol) was added to a suspension of5-chloro-7-(6-methoxypyrimidin-4-yl)-1H-indole (0.339 g, 1.305 mmol) andK₂CO₃ (0.902 g, 6.53 mmol) in DMSO (5.22 mL) at rt. After stirringovernight, the reaction mixture was partitioned between dilute NH₄Clsolution and EtOAc. The organic layer was washed dilute NaHCO₃ andNa₂S₂O₃ solution, NaHCO₃, brine, then dried over MgSO₄, filtered andevaporated to dryness. The residue was dissolved in AcOH (5 mL) andtreated with 45% aq HBr i (1.73 mL, 14.36 mmol) and heated to 85° C.After 2 h, the reaction was cooled to rt, then concentrated to drynessand the material was carried forward to the reaction. MS(ESI) m/z: 260(M+H)⁺.

293D. Preparation of(9R,13S)-13-[4-(5-chloro-1-methyl-1H-indol-7-yl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate

(9R,13S)-13-[4-(5-Chloro-1-methyl-1H-indol-7-yl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate (4 mg, 18%) was prepared in a similar manner as Example56 using 6-(5-chloro-1-methyl-1H-indol-7-yl)pyrimidin-4-ol and(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one,prepared as described in Intermediate 30. MS(ESI) m/z: 578 (M+H)⁺. ¹HNMR (400 MHz, DMSO-d₆) δ 9.36 (s, 1H), 8.98 (s, 1H), 8.70 (d, J=5.1 Hz,1H), 7.85 (s, 1H), 7.69 (s, 1H), 7.65 (d, J=2.0 Hz, 1H), 7.39-7.35 (m,2H), 7.03 (d, J=2.0 Hz, 1H), 6.57 (s, 1H), 6.46 (d, J=3.1 Hz, 1H),5.94-5.90 (m, 1H), 3.53 (s, 3H), 2.63-2.60 (m, 1H), 2.35-2.30 (m, 1H),2.06-2.02 (m, 1H), 1.95-1.88 (m, 1H), 1.46-1.40 (m, 1H), 1.34-1.28 (m,1H), 0.82 (d, J=6.8 Hz, 3H), 0.37-0.29 (m, 1H). Analytical HPLC (MethodA): RT=9.19 min, purity=>95%; Factor XIa Ki=390 nM.

Example 294 Preparation of(9R,13S)-13-{4-[5-chloro-2-(2-hydroxyethyl)-2H-indazol-7-yl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

294A. Preparation of5-chloro-2-(2-methoxyethyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazole

5-Chloro-2-(2-methoxyethyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazolewas prepared in a similar manner as Example 292C replacing7-bromo-5-chloro-1-(2-methoxyethyl)-1H-indazole, prepared as describedin Example 292B with 7-bromo-5-chloro-2-(2-methoxyethyl)-2H-indazole,prepared as described in Example 292C. MS(ESI) m/z: 337 (M+H)⁺.

294B. Preparation of5-chloro-2-(2-methoxyethyl)-7-(6-methoxypyrimidin-4-yl)-2H-indazole

5-Chloro-2-(2-methoxyethyl)-7-(6-methoxypyrimidin-4-yl)-2H-indazole (300mg, 26%) was prepared in a similar manner as described in Example 292Dusing5-chloro-2-(2-methoxyethyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazole.MS(ESI) m/z: 319 (M+H)⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.87 (d, J=1.1 Hz,1H), 8.39 (t, J=1.8 Hz, 2H), 8.09 (s, 1H), 7.75 (d, J=2.0 Hz, 1H), 4.63(t, J=5.2 Hz, 2H), 4.06 (s, 3H), 3.92-3.88 (m, 2H), 3.35 (s, 3H).

294C. Preparation of6-(5-chloro-2-(2-hydroxyethyl)-2H-indazol-7-yl)pyrimidin-4-ol

6-(5-Chloro-2-(2-hydroxyethyl)-2H-indazol-7-yl)pyrimidin-4-ol, (50 mg,18%) was prepared in a similar manner as Example 292E using5-chloro-2-(2-methoxyethyl)-7-(6-methoxypyrimidin-4-yl)-2H-indazole.MS(ESI) m/z: 291 (M+H)⁺ and 293 (M+2+H)⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.71(s, 1H), 8.46 (s, 1H), 8.22 (d, J=2.0 Hz, 1H), 8.05 (s, 1H), 8.01 (d,J=1.8 Hz, 1H), 4.65 (t, J=5.2 Hz, 2H), 4.14-4.09 (m, 2H).

294D. Preparation of(9R,13S)-13-{4-[5-chloro-2-(2-hydroxyethyl)-2H-indazol-7-yl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate

(9R,13S)-13-{4-[5-Chloro-2-(2-hydroxyethyl)-2H-indazol-7-yl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate was prepared (2 mg, 8.8%) in a similar manner asExample 56 using6-(5-chloro-2-(2-hydroxyethyl)-2H-indazol-7-yl)pyrimidin-4-ol and(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one,prepared as described in Intermediate 30. MS(ESI) m/z: 609 (M+H)⁺. ¹HNMR (400 MHz, DMSO-d₆) δ 9.36 (s, 1H), 9.00 (s, 1H), 8.69 (d, J=5.1 Hz,1H), 8.49 (s, 1H), 8.21 (d, J=2.2 Hz, 1H), 8.03-7.97 (m, 2H), 7.85 (s,1H), 7.68 (s, 1H), 7.37 (d, J=6.2 Hz, 1H), 5.92-5.89 (m, 1H), 4.48 (t,J=5.3 Hz, 2H), 3.82 (t, J=5.3 Hz, 2H), 2.62-2.59 (m, 1H), 2.34-2.29 (m,1H), 2.07-2.02 (m, 1H), 1.91-1.87 (m, 1H), 1.47-1.41 (m, 1H), 1.34-1.29(m, 1H), 0.83 (d, J=6.8 Hz, 3H), 0.38-0.30 (m, 1H). Analytical HPLC(Method A): RT=7.86 min, purity=>95%; Factor XIa Ki=6,100 nM.

Example 295 Preparation of(9R,13S)-13-[4-(6-chloro-1-methyl-1H-indazol-4-yl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

295A. Preparation of6-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole

6-Chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole wasprepared in a similar manner as described in Example 293A replacing7-bromo-5-chloro-1H-indole with 4-bromo-6-chloro-1H-indazole. MS(ESI)m/z: 197 (M-C₆H₁₀+H)⁺.

295B. Preparation of 6-chloro-4-(6-methoxypyrimidin-4-yl)-1H-indazole

6-Chloro-4-(6-methoxypyrimidin-4-yl)-1H-indazole (183 mg, 33%) wasprepared in a similar manner as described in Example 293B using6-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole.MS(ESI) m/z: 261 (M+H)⁺.

295C. Preparation of 6-(6-chloro-1-methyl-1H-indazol-4-yl)pyrimidin-4-ol

MeI (0.12 mL, 1.825 mmol) was added to a suspension of6-chloro-4-(6-methoxypyrimidin-4-yl)-1H-indazole (0.183 g, 0.702 mmol)and K₂CO₃ (0.485 g, 3.51 mmol) in DMSO (2.81 mL) at rt. After stirringovernight, the reaction mixture was partitioned between dilute aq NH₄Clsolution and EtOAc. The organic layer was washed with dilute NaHCO₃ andNa₂S₂O₃ solution, NaHCO₃, brine, then dried over MgSO₄, filtered, andevaporated to dryness. This mixture of regioisomers (2:1) was carriedforward to the next reaction. The residue was dissolved in AcOH (3 mL),treated with 45% aq HBr (0.932 ml, 7.72 mmol), and heated to 85° C.After 1 h, the reaction mixture was concentrated to dryness, and thecrude reaction mixture was purified by reverse phase chromatography(PHENOMENEX® Luna Axia C18 5μ 30×100 mm column, 10-minute gradient;Solvent A: 30% ACN—70% H₂O— 0.1% TFA; Solvent B: 80% ACN—20% H₂O— 0.1%TFA) to give the desired isomer, 6-(6-chloro-1-methyl-1H-indazol-4-yl)pyrimidin-4-ol (0.127 g, 69.4%) as a white solid and undesired isomer,6-(6-chloro-2-methyl-2H-indazol-4-yl)pyrimidin-4-ol (0.051 g, 27.9%) asan off-white solid. The methyl group is more downfield for the undesiredisomer than for the desired. MS(ESI) m/z: 261 (M+H)⁺. ¹H NMR: (400 MHz,DMSO-d₆) d 12.69 (br. s., 1H), 8.51 (d, J=0.9 Hz, 1H), 8.37 (d, J=0.7Hz, 1H), 8.03-7.99 (m, 1H), 7.77-7.74 (m, 1H), 6.99 (d, J=0.9 Hz, 1H),4.09 (s, 3H).

295D. Preparation of(9R,13S)-13-[4-(6-chloro-1-methyl-1H-indazol-4-yl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate

(9R,13S)-13-[4-(6-Chloro-1-methyl-1H-indazol-4-yl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate was prepared (1.5 mg, 6.9%) in a similar manner asExample 56 using 6-(6-chloro-1-methyl-1H-indazol-4-yl) pyrimidin-4-oland(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one,prepared as described in Intermediate 30. MS(ESI) m/z: 579 (M+H)⁺.Analytical HPLC (Method A): RT=8.40 min, purity=>95%; Factor XIaKi=7,400 nM.

Example 296 Preparation of(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-4-(6-hydroxypyridin-3-yl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2,5,14,16-pentaen-8-one

(9R,13S)-13-{4-[5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-4-(6-methoxypyridin-3-yl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2,5,14,16-pentaen-8-one,prepared as described in Example 233, was dissolved in THF (1 mL) andHCl (0.5 mL). The solution was heated to 70° C. for 8 h, then cooled tort, concentrated and purified by reverse phase chromatography to give(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-4-(6-hydroxypyridin-3-yl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2,5,14,16-pentaen-8-onetrifluoroacetate (2.2 mg, 21%). MS(ESI) m/z: 669.3 (M+H)⁺. ¹H NMR (500MHz, DMSO-d₆) δ 9.55-9.54 (m, 1H), 9.52 (s, 1H), 8.76-8.65 (m, 2H), 8.58(d, J=5.2 Hz, 1H), 8.38 (s, 1H), 8.03 (d, J=9.8 Hz, 1H), 7.98 (d, J=2.7Hz, 1H), 7.92 (d, J=2.1 Hz, 1H), 7.87 (s, 1H), 7.84-7.78 (m, 1H), 7.73(d, J=8.5 Hz, 1H), 7.56 (d, J=5.2 Hz, 1H), 6.57 (d, J=9.8 Hz, 1H), 6.36(s, 1H), 6.03-5.90 (m, 1H), 2.33-2.15 (m, 2H), 1.93-1.78 (m, 1H),1.63-1.50 (m, 1H), 1.49-1.35 (m, 1H), 0.94 (d, J=6.7 Hz, 3H), 0.65-0.49(m, 1H). Analytical HPLC (Method C): RT=1.41 min, purity=95%; Factor XIaKi=1 nM, Plasma Kallikrein Ki=43 nM.

Example 297 Preparation of(9R,13S)-13-{4-[5-chloro-2-(1,2,3-thiadiazol-4-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

297A. Preparation of1-[4-chloro-2-(6-methoxypyrimidin-4-yl)phenyl]ethan-1-one

A solution of 4-(2-bromo-5-chlorophenyl)-6-methoxypyrimidine (0.173 g,0.578 mmol), CeF (0.351 g, 2.310 mmol) in ClCH₂CH₂Cl (3 mL) was purgedwith Ar, and Pd(PPh₃)₄ (0.033 g, 0.029 mmol) and1-(trimethylsilyl)ethanone (0.165 mL, 1.155 mmol) were added. Thereaction mixture was purged with Ar, sealed and heated at 75° C. for 2days then cooled down to rt. Hexane (1 ml) was added, reaction mixturewas filtered through a pad of CELITE®, rinsed with 10 ml EtOAc, filtrateconcentrated. Purification by normal phase chromatography gave1-[4-chloro-2-(6-methoxypyrimidin-4-yl)phenyl]ethan-1-one (0.057 g, 38%yield). MS(ESI) m/z: 263.08 (M+H)⁺.

297B. Preparation ofN′-{1-[4-chloro-2-(6-methoxypyrimidin-4-yl)phenyl]ethenyl}ethoxycarbohydrazide

To a solution of 1-(4-chloro-2-(6-methoxypyrimidin-4-yl)phenyl)ethanone(0.057 g, 0.217 mmol) and ethyl hydrazinecarboxylate (0.022 g, 0.217mmol) in EtOH (3 mL) was added 2 drops of conc. aq HCl. The reaction washeated at 75° C. for 2 h. After this time, the reaction mixture wasconcentrated to yield crude solidN′-{1-[4-chloro-2-(6-methoxypyrimidin-4-yl)phenyl]ethenyl}ethoxycarbohydrazide.MS(ESI) m/z: 349.4 (M+H)⁺.

297C. Preparation of4-[5-chloro-2-(1,2,3-thiadiazol-4-yl)phenyl]-6-methoxypyrimidine

ToN′-{1-[4-chloro-2-(6-methoxypyrimidin-4-yl)phenyl]ethenyl}ethoxycarbohydrazide(0.076 g, 0.217 mmol) in a vial was added SOCl₂ (0.32 ml, 4.34 mmol),and the resulting solution was stirred at rt for 30 min, then heated at60° C. for 1 h. After this time, the solution was cooled to rt. To thereaction mixture was added MeOH, and the solution was concentrated. Theresidue was purified by reverse phase chromatography to afford4-(4-chloro-2-(6-methoxypyrimidin-4-yl)phenyl)-1,2,3-thiadiazole (0.017g, 26% yield) as a yellow solid. MS(ESI) m/z: 305.0 (M+H)⁺. ¹H NMR (400MHz, CD₃OD) δ 8.87 (s, 1H), 8.63 (d, J=1.1 Hz, 1H), 7.86 (d, J=8.6 Hz,1H), 7.76 (d, J=2.0 Hz, 1H), 7.71 (dd, J=8.4, 2.2 Hz, 1H), 6.82 (d,J=1.1 Hz, 1H), 4.02 (s, 3H).

297D. Preparation of6-[5-chloro-2-(1,2,3-thiadiazol-4-yl)phenyl]pyrimidin-4-ol

4-(4-Chloro-2-(6-methoxypyrimidin-4-yl)phenyl)-1,2,3-thiadiazole (0.059g, 0.194 mmol) in AcOH (2 ml) was added 48% aq HBr (1.1 ml, 9.68 mmol),and the solution was heated at 85° C. for 1 h then cooled to rt. Thereaction mixture was concentrated. The residue was dissolved in EtOAc,washed with sat aq NaHCO₃, brine, dried over MgSO₄, filtered andconcentrated to give 6-(5-chloro-2-(1,2,3-thiadiazol-4-yl)phenyl)pyrimidin-4-ol (0.053 g, 94% yield) as an off-white solid.MS(ESI) m/z: 291.0 (M+H)⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.84 (s, 1H), 7.94(s, 1H), 7.70 (d, J=8.1 Hz, 1H), 7.61 (d, J=2.0 Hz, 1H), 7.55 (dd,J=8.4, 2.2 Hz, 1H), 6.27 (d, J=0.7 Hz, 1H).

297E. Preparation of(9R,13S)-13-{4-[5-chloro-2-(1,2,3-thiadiazol-4-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate

(9R,13S)-13-{4-[5-Chloro-2-(1,2,3-thiadiazol-4-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate (0.006 g, 7.7%) was prepared according to theprocedures described in Example 56 by using(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one,prepared as described in Intermediate 30, and6-[5-chloro-2-(1,2,3-thiadiazol-4-yl)phenyl]pyrimidin-4-ol, MS(ESI) m/z:609.1 (M+H)⁺. ¹H NMR (400 MHz, CD₃OD δ 8.93 (s, 1H), 8.87 (s, 1H), 8.74(d, J=5.1 Hz, 1H), 7.82-7.63 (m, 6H), 7.54-7.50 (m, 1H), 6.38 (s, 1H),6.02 (dd, J=12.8, 4.8 Hz, 1H), 2.78-2.65 (m, 1H), 2.35-2.22 (m, 1H),2.10-1.96 (m, 2H), 1.65-1.54 (m, 1H), 1.53-1.42 (m, 1H), 0.99 (d, J=7.0Hz, 3H), 0.63 (br. s., 1H). Analytical HPLC (Method A): RT=8.80 min,purity>96%; Factor XIa Ki=1.6 nM, Plasma Kallikrein Ki=520 nM.

Example 298 Preparation of(9R,13S)-13-(4-{3-chloro-2-fluoro-6-[4-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

298A. Preparation of4-(3-chloro-2-fluoro-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)-6-methoxypyrimidine

4-(3-Chloro-2-fluoro-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)-6-methoxypyrimidine(42 mg, 25% yield) was prepared in a similar manner as the proceduredescribed in Example 238C, by replacing 1H-pyrazole-4-carbonitrile with4-(trifluoromethyl)-1H-pyrazole (37.3 mg, 0.274 mmol). MS(ESI) m/z:373.3 (M+H)⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.68 (d, J=1.1 Hz, 1H), 7.76 (s,1H), 7.70 (s, 1H), 7.62 (dd, J=8.6, 7.7 Hz, 1H), 7.36 (dd, J=8.7, 1.7Hz, 1H), 6.78 (t, J=1.2 Hz, 1H), 4.01 (s, 3H).

298B. Preparation of6-(3-chloro-2-fluoro-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)pyrimidin-4-ol

6-(3-Chloro-2-fluoro-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)pyrimidin-4-ol(0.017 g, 42.1% yield) was prepared in a similar manner as the proceduredescribed for the preparation of1-[4-chloro-2-(6-hydroxypyrimidin-4-yl)phenyl]-1H-1,2,3-triazole-4-carbonitrileas described in Intermediate 18C, by replacing1-[4-chloro-2-(6-methoxypyrimidin-4-yl)phenyl]-1H-1,2,3-triazole-4-carbonitrilewith4-(3-chloro-2-fluoro-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)-6-methoxypyrimidine(0.042 g, 0.113 mmol). MS(ESI) m/z: 359.4 (M+H)⁺. ¹H NMR (400 MHz,CD₃OD) δ 8.36 (d, J=0.9 Hz, 1H), 8.09 (d, J=1.1 Hz, 1H), 7.85 (s, 1H),7.81-7.74 (m, 1H), 7.50 (dd, J=8.7, 1.7 Hz, 1H), 6.50 (t, J=1.1 Hz, 1H).

298C. Preparation of(9R,13S)-13-(4-{3-chloro-2-fluoro-6-[4-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

(9R,13S)-13-(4-{3-Chloro-2-fluoro-6-[4-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(13 mg, 37% yield) was prepared in a similar manner as the proceduredescribed in Example 56, by replacing6-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}pyrimidin-4-olwith6-(3-chloro-2-fluoro-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)pyrimidin-4-ol(17 mg, 0.047 mmol). MS(ESI) m/z: 641.2 (M+H)⁺. ¹H NMR (400 MHz, CD₃OD)δ 9.40 (s, 1H), 8.85 (br. s., 1H), 8.72 (d, J=4.8 Hz, 1H), 8.31 (s, 1H),7.85-7.74 (m, 2H), 7.69 (s, 1H), 7.55-7.44 (m, 3H), 6.53 (s, 1H), 6.02(dd, J=12.4, 3.9 Hz, 1H), 4.05 (s, 3H), 2.70 (td, J=6.6, 3.1 Hz, 1H),2.37-2.22 (m, 1H), 2.15-1.91 (m, 2H), 1.69-1.54 (m, 1H), 1.53-1.39 (m,1H), 1.01 (d, J=6.8 Hz, 3H), 0.70 (m., 1H). Analytical HPLC (Method A):RT=8.81 min, purity=99%; Factor XIa Ki=3.8 nM, Plasma KallikreinKi=1,200 nM.

Example 299 Preparation of(9R,13S)-13-[4-(3-chloro-2,6-difluorophenyl)-6-oxo-1,6-dihydropyrimidin-1-yl]-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

299A. Preparation of(9R,13S)-13-[4-(3-chloro-2,6-difluorophenyl)-6-oxo-1,6-dihydropyrimidin-1-yl]-9-methyl-3-{[2-(trimethylsilyl)ethoxy]methyl}-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

(9R,13S)-13-[4-(3-Chloro-2,6-difluorophenyl)-6-oxo-1,6-dihydropyrimidin-1-yl]-9-methyl-3-{[2-(trimethylsilyl)ethoxy]methyl}-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(78 mg, 89% yield) was prepared in a similar manner as the proceduresdescribed in Example 56, by using6-(3-chloro-2,6-difluorophenyl)pyrimidin-4-ol (0.033 g, 0.137 mmol),prepared as described in Intermediate 4, and(9R,13S)-9-methyl-3-{[2-(trimethylsilyl)ethoxy]methyl}-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(0.057 g, 0.137 mmol), prepared as described in Intermediate 19. MS(ESI)m/z: 641.6 [M+H]+.

299B. Preparation of(9R,13S)-13-[4-(3-chloro-2,6-difluorophenyl)-6-oxo-1,6-dihydropyrimidin-1-yl]-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate

To a solution of(9R,13S)-13-[4-(3-chloro-2,6-difluorophenyl)-6-oxo-1,6-dihydropyrimidin-1-yl]-9-methyl-3-{[2-(trimethylsilyl)ethoxy]methyl}-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(78 mg, 0.122 mmol), in DCM (1.6 mL) was added TFA (0.4 mL, 5.19 mmol)and the resulting solution was stirred at rt for 30 min. The reactionmixture was then concentrated and the residue was purified by prep HPLCpurification to give(9R,13S)-13-[4-(3-chloro-2,6-difluorophenyl)-6-oxo-1,6-dihydropyrimidin-1-yl]-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate (70 mg, 0.112 mmol, 92% yield). ¹H NMR (500 MHz,DMSO-d₆) δ 9.31 (s, 1H), 8.95 (s, 1H), 8.57 (br. s., 1H), 7.92-7.71 (m,3H), 7.48 (d, J=4.0 Hz, 1H), 7.31 (t, J=8.9 Hz, 1H), 6.70 (s, 1H), 5.99(br. s., 1H), 2.73 (br. s., 1H), 2.30 (br. s., 2H), 2.01-1.88 (m, 1H),1.60-1.37 (m, 2H), 0.93 (d, J=6.7 Hz, 3H), 0.64 (br. s., 1H). MS(ESI)m/z: 511.3 [M+H]⁺. Analytical HPLC (Method B): RT=1.47 min,purity=94.0%; Factor XIa Ki=970 nM.

Example 300 Preparation of(9R,13S)-13-{4-[5-chloro-2-(1,2,3-thiadiazol-4-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

(9R,13S)-13-{4-[5-Chloro-2-(1,2,3-thiadiazol-4-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate (0.0072 g, 37.8%) was prepared in a similar manner asthe procedure described in Example 297 using(9R,13S)-13-amino-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one,prepared as described in Intermediate 32. MS(ESI) m/z: 573.2 (M+H)⁺. ¹HNMR (400 MHz, CD₃OD) δ 8.98 (s, 1H), 8.85 (s, 1H), 8.76 (d, J=5.3 Hz,1H), 7.82 (d, J=8.1 Hz, 1H), 7.78 (s, 1H), 7.76 (d, J=2.2 Hz, 1H), 7.68(dd, J=8.1, 2.2 Hz, 1H), 7.61 (dd, J=5.3, 1.5 Hz, 1H), 7.52 (s, 1H),6.40 (s, 1H), 5.99 (dd, J=12.8, 4.4 Hz, 1H), 4.07 (s, 3H), 2.77-2.67 (m,1H), 2.39-2.27 (m, 1H), 2.14-2.00 (m, 2H), 1.69-1.56 (m, 1H), 1.55-1.41(m, 1H), 1.03 (d, J=7.0 Hz, 3H), 0.76 (br. s., 1H). Analytical HPLC(Method A): RT=7.46 min, purity>99%; Factor XIa Ki=1.5 nM, PlasmaKallikrein Ki=280 nM.

Example 301 Preparation of(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-4-(2-hydroxypyridin-4-yl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2,5,14,16-pentaen-8-one

(9R,13S)-13-(4-{5-Chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-4-(2-methoxypyridin-4-yl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2,5,14,16-pentaen-8-one,prepared as described in Example 323, (0.02 g, 0.027 mmol) was dissolvedin THF (2 mL) and HCl (500 μl, 6.00 mmol) and heated to 70° C. for 16 h.The solvents were concentrated. The residue was purified by reversephase chromatography to give(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-4-(2-hydroxypyridin-4-yl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2,5,14,16-pentaen-8-one.(1.1 mg, 6%). MS(ESI) m/z: 703.0 (M+H)⁺. ¹H NMR (500 MHz, DMSO-d₆) δ9.58 (s, 1H), 9.33-9.18 (m, 1H), 8.84-8.69 (m, 2H), 8.59 (d, J=4.6 Hz,1H), 7.98 (br. s., 1H), 7.95-7.79 (m, 3H), 7.71-7.51 (m, 2H), 6.97-6.78(m, 2H), 6.59-6.47 (m, 1H), 6.04 (br. s., 1H), 2.80 (br. s., 1H), 2.27(br. s., 2H), 1.97-1.75 (m, 2H), 1.57 (br. s., 1H), 1.42 (br. s., 1H),0.94 (d, J=6.7 Hz, 3H), 0.53 (br. s., 1H). Analytical HPLC (Method C):RT=1.58 min, purity=100%; Factor XIa Ki=0.16 nM, Plasma Kallikrein Ki=8nM.

Example 302 Preparation of(9R,13S)-13-[4-(3-chloro-2,6-difluorophenyl)-6-oxo-1,6-dihydropyrimidin-1-yl]-9-methyl-4-(pyrimidin-5-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2,5,14,16-pentaen-8-one

(9R,13S)-13-[4-(3-Chloro-2,6-difluorophenyl)-6-oxo-1,6-dihydropyrimidin-1-yl]-9-methyl-4-(pyrimidin-5-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2,5,14,16-pentaen-8-onetrifluoroacetate (13.7 mg, 0.019 mmol, 33% yield) was prepared in asimilar manner as the procedure described in Example 216, by using5-iodopyrimidine (24 mg, 0.117 mmol) and(9R,13S)-13-[4-(3-chloro-2,6-difluorophenyl)-6-oxo-1,6-dihydropyrimidin-1-yl]-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate (30 mg, 0.059 mmol), as described in Example 299. ¹HNMR (500 MHz, DMSO-d₆) δ 9.58 (s, 1H), 9.35 (s, 2H), 9.15 (s, 1H), 8.97(s, 1H), 8.76 (s, 1H), 8.63 (d, J=4.9 Hz, 1H), 7.92 (s, 1H), 7.74 (td,J=8.7, 5.8 Hz, 1H), 7.61 (d, J=4.9 Hz, 1H), 7.29 (t, J=9.0 Hz, 1H), 6.69(s, 1H), 6.01 (d, J=11.6 Hz, 1H), 2.77 (br. s., 1H), 2.28 (br. s., 2H),1.99-1.88 (m, 1H), 1.54 (br. s., 1H), 1.43 (br. s., 1H), 0.91 (d, J=6.7Hz, 3H), 0.55 (br. s., 1H). MS(ESI) m/z: 589.2 [M+H]⁺. Analytical HPLC(Method B): RT=1.64 min, purity=100.0%; Factor XIa Ki=100 nM, PlasmaKallikrein Ki=530 nM.

Example 303 Preparation of(9R,13S)-13-{4-[5-chloro-2-(pyridazin-4-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

To a degassed solution of(9R,13S)-13-[4-(5-chloro-2-iodophenyl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(20 mg, 0.033 mmol), prepared as described in Example 211,4-(tributylstannyl)pyridazine (18.01 mg, 0.049 mmol), CuI (1.24 mg, 6.51μmol), and CsF (9.88 mg, 0.065 mmol) in ACN (1 ml) was added Pd(Ph₃P)₄(3.76 mg, 3.25 μmol). After stirring at 45° C. for 2 h, the reaction wascooled to rt and concentrated. Purification by reverse phasechromatography afforded(9R,13S)-13-{4-[5-chloro-2-(pyridazin-4-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate (14.9 mg, 67% yield). MS(ESI) m/z: 567.35 (M+H)⁺. ¹HNMR (500 MHz, DMSO-d₆) δ 9.27-9.19 (m, 2H), 9.09 (br. s., 1H), 8.76 (s,1H), 8.67 (d, J=5.2 Hz, 1H), 7.80 (d, J=1.8 Hz, 1H), 7.74 (dd, J=8.2,2.1 Hz, 1H), 7.68-7.56 (m, 4H), 7.48 (s, 1H), 6.50 (s, 1H), 5.92-5.83(m, 1H), 4.01 (s, 3H), 2.69-2.60 (m, 1H), 2.31-2.22 (m, 1H), 2.14-2.04(m, 1H), 1.89-1.78 (m, 1H), 1.53-1.42 (m, 1H), 1.38-1.26 (m, 1H), 0.88(d, J=6.7 Hz, 3H), 0.50-0.32 (m, 1H). Analytical HPLC (Method C):RT=1.28 min, 100% purity; Factor XIa Ki=110 nM, Plasma KallikreinKi=9,300 nM.

Example 304 Preparation of(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-4-(2-hydroxypyrimidin-5-yl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2,5,14,16-pentaen-8-one

(9R,13S)-13-{4-[5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-4-(2-hydroxypyrimidin-5-yl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2,5,14,16-pentaen-8-onetrifluoroacetate was prepared in a similar manner as the proceduredescribed in Example 216, by using 5-iodopyrimidin-2-ol (9.63 mg, 0.043mmol) to give(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-4-(2-hydroxypyrimidin-5-yl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2,5,14,16-pentaen-8-onetrifluoroacetate (0.9 mg, 1.032 μmol, 2% yield). ¹H NMR (500 MHz,DMSO-d₆) δ 9.44 (s, 1H), 8.85-8.66 (m, 4H), 8.55 (d, J=4.9 Hz, 1H), 8.40(s, 1H), 7.95-7.83 (m, 2H), 7.81-7.66 (m, 2H), 7.53 (d, J=4.6 Hz, 1H),6.34 (s, 1H), 5.95 (br. s., 1H), 2.74 (br. s., 1H), 2.24 (d, J=14.6 Hz,2H), 1.80 (br. s., 1H), 1.51 (br. s., 1H), 1.37 (br. s., 1H), 0.89 (d,J=6.4 Hz, 3H), 0.50 (br. s., 1H). MS(ESI) m/z: 670.2 [M+H]⁺. AnalyticalHPLC (Method B): RT=1.39 min, purity=90.0%; Factor XIa Ki=0.17 nM,Plasma Kallikrein Ki=14 nM.

Example 305 Preparation of(10R,14S)-14-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-10-methyl-5,8,17-triazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-9-one

305A. Preparation of (S)-tert-butyl(1-(5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)pyridin-3-yl)but-3-en-1-yl)carbamate

To a solution of 5,5,5′,5′-tetramethyl-2,2′-bi(1,3,2-dioxaborinane) (2.9g, 12.84 mmol) and (S)-tert-butyl(1-(5-bromopyridin-3-yl)but-3-en-1-yl)carbamate (3.0 g, 9.17 mmol) intoluene (38.8 mL) were added KOAc (2.70 g, 27.5 mmol) and Pd (dppf)Cl₂.CH₂Cl₂ Adduct (0.599 g, 0.733 mmol). The reaction was purged with Arfor 10 min and then heated at 90° C. for 12 h. The reaction mixture wasdiluted with EtOAc and then filtered through CELITE®. The filtrate waswashed with water, brine, dried over Na₂SO₄, filtered, and concentrated.MS(ESI) m/z: 293 (M-C₆H₁₀+H)⁺.

305B. Preparation of (S)-tert-butyl(1-(3′-amino-[3,4′-bipyridin]-5-yl)but-3-en-1-yl)carbamate

(S)-tert-Butyl(1-(5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)pyridin-3-yl)but-3-en-1-yl)carbamate(1.5 g, 4.16 mmol), 4-bromopyridin-3-amine (0.72 g, 4.16 mmol), 4 MNaHCO₃ (3.12 mL, 12.49 mmol) were added to dioxane (5 mL) and purgedwith Ar. After 15 min, Pd(PPh₃)₄ (0.241 g, 0.208 mmol) was added and themixture heated at 90° C. overnight. The reaction mixture was dilutedwith water (100 ml) and extracted with EtOAc (2×50 ml), washed withbrine, dried and evaporated to a black oil and was carried forward tothe next reaction. MS(ESI) m/z: 341.2 (M+H)⁺.

305C. Preparation of tert-butyl((S)-1-(3′-((R)-2-methylbut-3-enamido)-[3,4′-bipyridin]-5-yl)but-3-en-1-yl)carbamate

(R)-2-Methylbut-3-enoic acid (0.576 g, 5.76 mmol), (S)-tert-butyl(1-(3′-amino-[3,4′-bipyridin]-5-yl)but-3-en-1-yl)carbamate (1.4 g, 4.11mmol), pyridine (0.998 ml, 12.34 mmol) in EtOAc (43.8 ml) was cooled to0° C. T3P® (50% wt in EtOAc) (5.23 g, 8.23 mmol) was added and thesolution allowed to gradually come to rt. After 3 h, reaction mixturewas concentrated and the residue purified by normal phase chromatographyusing EtOAc and MeOH as eluants to give tert-butyl((S)-1-(3′-((R)-2-methylbut-3-enamido)-[3,4′-bipyridin]-5-yl)but-3-en-1-yl)carbamate(747 mg, 43%) as a brown oil. MS(ESI) m/z: 423.2 (M+H)⁺. ¹H NMR (500MHz, CDCl₃) δ 9.38 (br. s., 1H), 8.66 (s, 1H), 8.57-8.47 (m, 2H), 7.62(br. s., 1H), 7.44 (br. s., 1H), 7.20 (d, J=4.1 Hz, 1H), 5.86-5.76 (m,1H), 5.75-5.65 (m, 1H), 5.21-5.10 (m, 3H), 3.71 (d, J=11.0 Hz, 3H), 3.09(t, J=7.3 Hz, 1H), 2.66-2.46 (m, 2H), 1.44-1.39 (m, 9H), 1.28 (d, J=7.2Hz, 3H).

305D. Preparation of tert-butylN-[(10R,11E,14S)-10-methyl-9-oxo-5,8,17-triazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,11,15,17-heptaen-14-yl]carbamate

tert-Butyl((S)-1-(3′-((R)-2-methylbut-3-enamido)-[3,4′-bipyridin]-5-yl)but-3-en-1-yl)carbamate(0.747 g, 1.768 mmol) and pTsOH (0.689 g, 3.62 mmol) were added to EtOAc(1040 mL) and heated to 60° C. while purging with Ar. After 1 h, SecondGeneration Grubbs Catalyst (0.600 g, 0.707 mmol) was added and themixture stirred at 60° C. overnight. The reaction was quenched with satNaHCO₃ (150 mL) and extracted with EtOAc (2×50 mL). The combined organiclayers were washed with brine (100 mL), dried (Na₂SO₄), filtered andconcentrated. The crude material was purified by normal phasechromatography DCM and MeOH as eluants to give tert-butylN-[(10R,11E,14S)-10-methyl-9-oxo-5,8,17-triazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,11,15,17-heptaen-14-yl]carbamate(0.180 g, 25.8% yield) as a tan solid. MS(ESI) m/z: 395.2 (M+H)⁺.

305E. Preparation of tert-butylN-[(10R,14S)-10-methyl-9-oxo-5,8,17-triazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-14-yl]carbamate

PtO₂ (10.36 mg, 0.046 mmol) was added to a solution of tert-butylN-[(10R,11E,14S)-10-methyl-9-oxo-5,8,17-triazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,11,15,17-heptaen-14-yl]carbamate(0.180 g, 0.456 mmol) in EtOH (20 mL) and subjected to a H₂ atmosphere(55 psi). After 3 h, the suspension was filtered through a plug ofCELITE® and the filtrate concentrated and carried forward to the nextreaction. MS(ESI) m/z: 397.2 (M+H)⁺.

305F. Preparation of(10R,14S)-14-amino-10-methyl-5,8,17-triazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-9-one

TFA (0.70 mL, 9.08 mmol) was added to a stirring solution of tert-butylN-[(10R,14S)-10-methyl-9-oxo-5,8,17-triazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-14-yl]carbamate(0.180 g, 0.454 mmol) in DCM (5 mL) at rt. After 2 h, the reactionmixture was concentrated to dryness. The residue was partitioned betweenEtOAc and sat NaHCO₃. The aqueous layer was extracted with EtOAc (2×).The combined organic layer was washed with brine, dried over Na₂SO₄,filtered, and concentrated to give(10R,14S)-14-amino-10-methyl-5,8,17-triazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-9-one(0.037 g, 27.5%) as a brown film. MS(ESI) m/z: 297.2 (M+H)⁺.

305G. Preparation of(10R,14S)-14-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-10-methyl-5,8,17-triazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2,4,6,15,17-hexaen-9-one,bis-trifluoroacetate

(10R,14S)-14-(4-{5-Chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-10-methyl-5,8,17-triazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2,4,6,15,17-hexaen-9-one,bis-trifluoroacetate was prepared (5.2 mg, 11%) in a similar manner asExample 56 using(10R,14S)-14-amino-10-methyl-5,8,17-triazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-9-oneand6-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}pyrimidin-4-ol,prepared as described in Intermediate 15. MS(ESI) m/z: 621.2 (M+H)⁺. ¹HNMR (400 MHz, DMSO-d₆) δ 9.69 (s, 1H), 9.19-9.13 (m, 1H), 8.64-8.55 (m,2H), 8.49 (s, 1H), 8.41-8.38 (m, 1H), 8.03 (s, 1H), 7.87-7.84 (m, 1H),7.79-7.73 (m, 2H), 7.64 (d, J=4.6 Hz, 1H), 6.42 (s, 1H), 5.51 (d, J=12.8Hz, 1H), 1.90-1.84 (m, 1H), 1.75-1.67 (m, 1H), 1.39-1.32 (m, 1H),1.14-1.02 (m, 2H), 0.95-0.85 (m, 3H). Analytical HPLC (Method A):RT=6.96 min, purity=93%; Factor XIa Ki=0.17 nM, Plasma Kallikrein Ki=25nM.

Example 306 Preparation of(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-4-(piperidin-4-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2,5,14,16-pentaen-8-one

(9R,13S)-13-{4-[5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one,prepared as described in Example 101, (0.020 g, 0.035 mmol), tert-butyl4-iodopiperidine-1-carboxylate (11 mg, 0.035 mmol), Cs₂CO₃ (0.023 g,0.069 mmol), and DMF (2 mL) were added to a vial with a Teflonseptum-sealed cap. The mixture was heated to 100° C. for 12 h, at whichpoint it was cooled to rt and DCM (2 mL) and TFA (1 mL) were added andstirred for 1 h at rt. The reaction was then concentrated and purifiedby reverse phase chromatography to give(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-4-(piperidin-4-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2,5,14,16-pentaen-8-onetrifluoroacetate (3 mg, 14%). MS(ESI) m/z: 659.1 (M+H)⁺. ¹H NMR (500MHz, DMSO-d₆) δ 9.42-9.30 (m, 1H), 8.72 (s, 2H), 8.60-8.50 (m, 1H), 7.93(s, 2H), 7.84 (s, 2H), 7.78-7.72 (m, 1H), 7.48-7.40 (m, 1H), 6.36 (s,1H), 6.05-5.85 (m, 1H), 4.64-4.45 (m, 1H), 3.17-3.02 (m, 2H), 2.82-2.70(m, 1H), 1.94-1.75 (m, 1H), 1.62-1.48 (m, 1H), 1.47-1.34 (m, 1H), 0.93(d, J=7.0 Hz, 3H), 0.70-0.49 (m, 1H). Analytical HPLC (Method C):RT=1.31 min, purity=100%; Factor XIa Ki=700 nM.

Example 307 Preparation of1-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}-3-fluorophenyl)-1H-pyrazole-4-carbonitrile

1-(4-Chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}-3-fluorophenyl)-1H-pyrazole-4-carbonitriletrifluoroacetate (2 mg, 43% yield) was prepared in a similar manner asthe procedure described in Example 56, by replacing6-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}pyrimidin-4-olwith1-(4-chloro-3-fluoro-2-(6-hydroxypyrimidin-4-yl)phenyl)-1H-pyrazole-4-carbonitrile(2 mg, 6.34 μmol) prepared as described in Example 238C. MS(ESI) m/z:598.1 (M+H)⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.93-8.67 (m, 2H), 8.47 (s, 1H),7.94 (s, 1H), 7.80 (dd, J=8.6, 7.7 Hz, 1H), 7.70 (s, 1H), 7.57-7.45 (m,3H), 6.54 (s, 1H), 6.00 (dd, J=12.8, 4.2 Hz, 1H), 4.05 (s, 3H), 2.71(td, J=6.6, 3.3 Hz, 1H), 2.37-2.23 (m, 1H), 2.13-1.96 (m, 2H), 1.69-1.55(m, 1H), 1.54-1.41 (m, 1H), 1.01 (d, J=7.0 Hz, 3H), 0.71 (m, 1H).Analytical HPLC (Method A): RT=7.58 min, purity=97.1%; Factor XIa Ki=2nM, Plasma Kallikrein Ki=1,500 nM.

Example 308 Preparation of(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-4-(1H-imidazol-4-yl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2,5,14,16-pentaen-8-one

(9R,13S)-13-{4-[5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-4-(1H-imidazol-4-yl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2,5,14,16-pentaen-8-onetrifluoroacetate was prepared in a similar manner as the proceduredescribed in Example 216, by using 4-iodo-1-trityl-1H-imidazole (18.9mg, 0.043 mmol) followed by deprotection using 50% TFA in DCM and Et₃SiHas scavenger to yield(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-4-(1H-imidazol-4-yl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2,5,14,16-pentaen-8-onetrifluoroacetate (3.3 mg, 3.5 μmol, 7% yield). ¹H NMR (400 MHz, CD₃OD) δ8.75 (s, 1H), 8.69-8.62 (m, 1H), 8.37 (s, 1H), 8.24 (s, 1H), 8.03-7.90(m, 3H), 7.79-7.74 (m, 1H), 7.73-7.66 (m, 2H), 7.55 (br. s., 1H), 6.41(s, 1H), 6.11 (d, J=9.2 Hz, 1H), 2.88 (d, J=12.1 Hz, 1H), 2.31 (d,J=12.3 Hz, 2H), 2.09 (d, J=12.8 Hz, 1H), 1.74 (br. s., 1H), 1.59 (br.s., 1H), 1.11 (d, J=6.8 Hz, 3H), 0.92 (br. s., 1H). MS(ESI) m/z: 642.2[M+H]⁺. Analytical HPLC (Method A): RT=5.74 min, purity=80.0%; FactorXIa Ki=1.9 nM, Plasma Kallikrein Ki=180 nM.

Example 309 Preparation of(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-4-(1H-1,2,4-triazol-5-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2,5,14,16-pentaen-8-one

(9R,13S)-13-{4-[5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-4-(1H-1,2,4-triazol-5-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2,5,14,16-pentaen-8-one(9 mg, 33%) as a light brown powder was prepared in a similar manner asthe procedure described in Example 216, by using5-iodo-1H-1,2,4-triazole. MS(ESI) m/z: 643.1 (M+H)⁺. ¹H NMR (500 MHz,CD₃OD) δ 8.76 (s, 1H), 8.67 (d, J=5.0 Hz, 1H), 8.58-8.48 (m, 1H), 8.41(s, 1H), 8.36 (s, 1H), 7.98 (s, 1H), 7.91 (d, J=2.2 Hz, 1H), 7.81-7.72(m, 2H), 7.67 (d, J=8.5 Hz, 1H), 6.40 (s, 1H), 6.18-6.04 (m, 1H),2.92-2.80 (m, 1H), 2.38-2.22 (m, 2H), 2.13-2.01 (m, 1H), 1.81-1.68 (m,1H), 1.65-1.52 (m, 1H), 1.10 (d, J=6.9 Hz, 3H), 0.91 (d, J=11.8 Hz, 2H).Analytical HPLC (Method A): RT=6.27 min, purity=95%; Factor XIa Ki=3 nM,Plasma Kallikrein Ki=220 nM.

Example 310 Preparation ofN-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)-2,2,2-trifluoroacetamide

310A. Preparation ofN-(4-chloro-2-(6-methoxypyrimidin-4-yl)phenyl)-2,2,2-trifluoroacetamide

TEA (0.71 ml, 5.09 mmol) was added to a solution of4-chloro-2-(6-methoxypyrimidin-4-yl)aniline (1 g, 4.24 mmol), preparedas described in Intermediate 8A, and TFAA (0.72 ml, 5.09 mmol) in DCM(25 ml). After stirring at rt for 1 h, the reaction was diluted withDCM, washed with sat NaHCO₃, brine, dried over Na₂SO₄, filtered, andconcentrated. A yellow solid was obtained asN-(4-chloro-2-(6-methoxypyrimidin-4-yl)phenyl)-2,2,2-trifluoroacetamide(1.4 g, 99% yield). MS(ESI) m/z: 332.0 (M+H)⁺.

310B. Preparation ofN-(4-chloro-2-(6-hydroxypyrimidin-4-yl)phenyl)-2,2,2-trifluoroacetamide

A clear yellow solution ofN-(4-chloro-2-(6-methoxypyrimidin-4-yl)phenyl)-2,2,2-trifluoroacetamide(1.4 g, 4.22 mmol) in HOAc (10 ml) and 48% aq HBr (2.39 ml, 21.10 mmol)was warmed to 60° C. for 3 h, then cooled to rt, and the reaction wasconcentrated. EtOAc (˜400 ml) was added to the residue, followed by satNaHCO₃. The layers were separated and the organic layer was washed withsat NaHCO₃, brine, dried over MgSO₄, filtered and concentrated. Theresidue was suspended in DCM, and the solid was filtered off. Thefiltrate was purified by normal phase chromatography to affordN-(4-chloro-2-(6-hydroxypyrimidin-4-yl)phenyl)-2,2,2-trifluoroacetamide(0.095 g, 7% yield) as a white solid. MS(ESI) m/z: 318.0 (M+H)⁺.

310C. Preparation ofN-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)-2,2,2-trifluoroacetamidetrifluoroacetate

N-(4-Chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)-2,2,2-trifluoroacetamidetrifluoroacetate (0.113 g, 63% yield) was prepared in a similar manneras the procedure described in Example 56, by usingN-(4-chloro-2-(6-hydroxypyrimidin-4-yl)phenyl)-2,2,2-trifluoroacetamide(0.095 g, 0.301 mmol). MS(ESI) m/z: 600.0 (M+H)⁺. ¹H NMR (400 MHz,DMSO-d₆) δ 12.37 (s, 1H), 9.23 (s, 1H), 9.07 (s, 1H), 8.70 (d, J=5.1 Hz,1H), 7.96-7.89 (m, 2H), 7.71 (s, 1H), 7.67-7.58 (m, 2H), 7.49 (s, 1H),6.89 (br. s., 1H), 5.95 (d, J=9.5 Hz, 1H), 4.02 (s, 3H), 2.72-2.62 (m,1H), 2.44-2.32 (m, 1H), 2.20-2.07 (m, 1H), 1.98-1.85 (m, 1H), 1.58-1.30(m, 2H), 0.91 (d, J=6.8 Hz, 3H), 0.58-0.39 (m, 1H). Analytical HPLC(Method A): RT=9.82 min, 100% purity; Factor XIa Ki=1.7 nM, PlasmaKallikrein Ki=180 nM.

Example 311 Preparation of(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-4-(2-hydroxypyridin-3-yl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2,5,14,16-pentaen-8-one

(9R,13S)-13-(4-{5-Chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-4-(2-methoxypyridin-3-yl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2,5,14,16-pentaen-8-one,prepared as described in Example 319, (0.02 g, 0.027 mmol) was dissolvedin THF (2 mL) and conc. HCl (500 μl, 6.00 mmol) and heated to 70° C. for16 h. The reaction was cooled to rt and the solution were concentrated.The residue was purified by reverse phase chromatography to give(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-4-(2-hydroxypyridin-3-yl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2,5,14,16-pentaen-8-one(15 mg, 64%). MS(ESI) m/z: 703.2 (M+H)⁺. ¹H NMR (500 MHz, CD₃OD) δ 8.84(s, 1H), 8.79 (s, 1H), 8.66 (s, 1H), 8.62 (d, J=5.0 Hz, 1H), 8.31 (dd,J=7.4, 1.9 Hz, 1H), 7.97 (s, 1H), 7.93 (d, J=2.2 Hz, 1H), 7.80-7.75 (m,1H), 7.75-7.68 (m, 2H), 7.48 (dd, J=6.6, 1.9 Hz, 1H), 6.58 (dd, J=7.4,6.3 Hz, 1H), 6.48 (d, J=0.6 Hz, 1H), 6.16-6.04 (m, 1H), 2.91-2.77 (m,1H), 2.34-2.21 (m, 2H), 2.11-2.00 (m, 1H), 1.79-1.66 (m, 1H), 1.63-1.51(m, 1H), 1.10 (d, J=6.9 Hz, 3H), 0.99-0.85 (n, 1H). Analytical HPLC(Method A): RT=7.36 min, purity=97.6%; Factor XIa Ki=19 nM, PlasmaKallikrein Ki=800 nM.

Example 312 Preparation of(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-3-(1H-pyrazol-3-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

(9R,13S)-13-{4-[5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-3-(1H-pyrazol-3-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate was prepared in a similar manner as the proceduredescribed in Example 216, by using 3-iodo-1-trityl-1H-pyrazole (18.9 mg,0.043 mmol) followed by deprotection using 50% TFA in DCM and Et₃SiH asscavenger to yield(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-4-(1H-imidazol-4-yl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2,5,14,16-pentaen-8-onetrifluoroacetate (5.3 mg, 3.5 μmol, 7% yield). ¹H NMR (500 MHz, DMSO-d₆)δ 9.31 (s, 1H), 8.69 (s, 1H), 8.58 (s, 1H), 8.52 (d, J=4.9 Hz, 1H), 8.33(s, 1H), 7.89 (br. s., 2H), 7.78 (d, J=8.5 Hz, 1H), 7.74-7.66 (m, 1H),7.53 (d, J=4.9 Hz, 1H), 7.24-6.96 (m, 3H), 6.37 (s, 1H), 5.80 (d, J=11.6Hz, 1H), 3.42-3.33 (m, 1H), 2.29 (br. s., 1H), 1.92 (d, J=11.3 Hz, 1H),1.79 (br. s., 1H), 1.48 (d, J=9.8 Hz, 1H), 1.30 (br. s., 1H), 1.14 (d,J=6.7 Hz, 3H), 0.97 (br. s., 1H). MS(ESI) m/z: 642.3 [M+H]⁺. AnalyticalHPLC (Method B): RT=1.48 min, purity=99.0%; Factor XIa Ki=28 nM, PlasmaKallikrein Ki=720 nM.

Example 313 Preparation of(9R,13S)-13-[4-(2-amino-5-chlorophenyl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

To the solution ofN-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)-2,2,2-trifluoroacetamide(0.111 g, 0.185 mmol), prepared as described in Example 310, in MeOH (2ml) was added 1.25 M HCl in MeOH (0.5 ml, 0.625 mmol). After stirring at75° C. for 1 h, the reaction was cooled to rt, concentrated andlyophilized overnight to give(9R,13S)-13-[4-(2-amino-5-chlorophenyl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onehydrochloride (0.1 g, 94% yield) as a yellow solid. From this material,10 mg was purified by reverse phase chromatography to afford(9R,13S)-13-[4-(2-amino-5-chlorophenyl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate. MS(ESI) m/z: 504.4 (M+H)⁺. ¹H NMR (500 MHz, CD₃OD) δ8.89 (br. s., 1H), 8.63 (d, J=5.0 Hz, 1H), 7.63 (s, 1H), 7.43-7.38 (m,2H), 7.33 (s, 1H), 7.04 (d, J=8.5 Hz, 1H), 6.68 (d, J=8.8 Hz, 1H), 6.59(s, 1H), 5.95 (d, J=9.9 Hz, 1H), 3.95 (s, 3H), 2.67-2.60 (m, 1H),2.31-2.21 (m, 1H), 2.06-1.91 (m, 2H), 1.59-1.34 (m, 2H), 0.92 (d, J=6.9Hz, 3H), 0.69-0.54 (m, 1H). Analytical HPLC (Method B): RT=1.45 min,100% purity; Factor XIa Ki=57 nM, Plasma Kallikrein Ki=2,400 nM.

Example 314 Preparation of(9R,13S)-13-(4-{5-chloro-2-[(pyrimidin-4-yl)amino]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

A mixture of(9R,13S)-13-[4-(2-amino-5-chlorophenyl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onehydrochloride (0.01 g, 0.017 mmol), 4-bromopyrimidine hydrochloride(6.78 mg, 0.035 mmol), prepared as described in Example 313, in EtOH (1ml) was microwaved at 150° C. for 30 min, cooled to rt and concentrated.Purification by reverse phase chromatography afforded(9R,13S)-13-(4-{5-chloro-2-[(pyrimidin-4-yl)amino]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate (6.3 mg, 45% yield). MS(ESI) m/z: 582.2 (M+H)⁺. ¹H NMR(500 MHz, CD₃OD) δ 8.88 (s, 1H), 8.61 (d, J=5.2 Hz, 1H), 8.56 (s, 1H),8.15 (d, J=6.1 Hz, 1H), 7.73-7.67 (m, 2H), 7.62 (s, 1H), 7.48 (dd,J=8.5, 2.5 Hz, 1H), 7.43-7.39 (m, 2H), 6.85 (d, J=6.9 Hz, 1H), 6.61 (s,1H), 5.89 (d, J=12.9 Hz, 1H), 3.97-3.92 (m, 3H), 2.66-2.59 (m, 1H),2.28-2.19 (m, 1H), 2.03-1.89 (m, 2H), 1.56-1.34 (m, 2H), 0.92 (d, J=7.2Hz, 3H), 0.71-0.56 (m, 1H). Analytical HPLC (Method C): RT=1.16 min,100% purity; Factor XIa Ki=6,000 nM.

Example 315 Preparation of(9R,13S)-13-{4-[2-(aminomethyl)-5-chlorophenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

315A. Preparation of tert-butyl4-chloro-2-(6-hydroxypyrimidin-4-yl)benzylcarbamate

In a microwave vial, was taken tert-butyl2-bromo-4-chlorobenzylcarbamate (0.78 g, 2.43 mmol) and dissolved indioxane (10 ml) and the solution was purged with Ar for 0.5 h. To thissolution was then added4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (0.93 g,3.64 mmol), followed by KOAc (0.64 g, 6.56 mmol) and Pd(dppf)Cl₂.CH₂Cl₂adduct (0.06 g, 0.07 mmol) and the reaction was sealed. The microwavevial was heated at 80° C. overnight. LCMS confirmed the formation ofdesired boronate/boronic acid and the reaction was cooled to rt. To thiswas added chloromethoxypyrimidine (0.351 g, 2.43 mmol) followed byaddition of 2 M aq Na₂CO₃ (3.04 ml) and the reaction mixture was purgedwith Ar for 0.5 h followed by the addition of Pd(dppf)Cl₂.CH₂Cl₂ adduct(0.06 g, 0.07 mmol) and the reaction was again sealed. The reaction washeated at 120° C. for 1 h then cooled to rt and the reaction wasquenched with water (100 ml). The organics were extracted with EtOAc(2×200 ml), dried and evaporated to a blackish oil. Purified via a 40 gsilica gel ISCO column and eluting with Hex:EtOAc gave pure product asan oily mass. LCMS m/z=350.08 (M+H)⁺.

315B. Preparation of tert-butyl4-chloro-2-(6-hydroxypyrimidin-4-yl)benzylcarbamate

The tert-butyl 4-chloro-2-(6-methoxypyrimidin-4-yl)benzylcarbamate wastaken in a small vial and to this was added AcOH (1 ml) followed by 48%aq HBr (0.1 ml), sealed and heated at 80° C. for 1 h. LCMS confirmedproduct peak and a mass of 336 (M+H)⁺. The solution was cooled andconcentrated under a stream of N₂ to a oily mass and dioxane (3 ml) wasadded at which point solid precipitated. The solution was decanted andthe residue was dissolved in DMF (3 ml) and transferred to the dioxane(2 ml) solution. To this was added Boc₂O (0.1 g) followed by TEA (2 ml)and the solution was stirred at rt overnight. To this solution was addedNaOH solution (1N, 5 ml) and the reaction was stirred at rt for 0.5 h.After this time, the reaction mixture was extracted with EtOAc (2×50ml). The combined organic layer was dried over MgSO₄, filtered andconcentrated to a dark brown oil. Purification via prep HPLC usingMeOH/water/TFA gradient afforded tert-butyl4-chloro-2-(6-hydroxypyrimidin-4-yl)benzylcarbamate (0.05 g). ¹H NMR(400 MHz, CDCl₃) δ 8.46-8.32 (m, 1H), 7.54-7.41 (m, 3H), 6.76-6.67 (m,1H), 4.31 (s, 2H), 1.44 (s, 9H). MS m/z=236.1 (M+H)⁺.

315C. Preparation of(9R,13S)-13-{4-[2-(aminomethyl)-5-chlorophenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

(9R,13S)-13-{4-[2-(Aminomethyl)-5-chlorophenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(4 mg, 42% yield) was prepared as a solid, via the coupling ofN-{[4-chloro-2-(6-hydroxypyrimidin-4-yl)phenyl]methyl}carbamate (0.005g, 0.015 mmol) and(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one (0.005 g, 0.015 mmol) using the HATU, DBU couplingmethodology described in Example 56. MS m/z=554.1 (M+H)⁺. ¹H NMR (500MHz, DMSO-d₆) δ 9.53-9.43 (m, 1H), 9.11-9.04 (m, 1H), 8.82-8.71 (m, 1H),8.42-8.23 (m, 1H), 7.98-7.83 (m, 1H), 7.79-7.70 (m, 1H), 7.68-7.59 (m,1H), 7.37-7.01 (m, 2H), 6.84-6.74 (m, 1H), 6.08-5.91 (m, 1H), 4.19-3.94(m, 2H), 2.77-2.63 (m, 1H), 2.34-2.22 (m, 1H), 2.13-1.86 (m, 2H),1.57-1.30 (m, 2H), 0.97-0.74 (d 3H), 0.53-0.27 (m, 1H). Analytical HPLC(Method B) RT=1.17 min, purity=96%: Factor XIa Ki=43 nM, PlasmaKallikrein Ki=4,900 nM.

Example 316 Preparation of(9R,13S)-13-{4-[5-chloro-2-(pyridin-2-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

(9R,13S)-13-{4-[5-Chloro-2-(pyridin-2-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate (13.3 mg, 51% yield) was prepared in a similar manneras the procedure described in Example 303, by replacing4-(tributylstannyl)pyridazine with 2-(tributylstannyl)pyridine (17.96mg, 0.049 mmol), and the reaction time was 2 h at 45° C. and then 6 h at90° C. MS(ESI) m/z: 566.15 (M+H)⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 9.23 (s,1H), 8.72 (br. s., 1H), 8.67 (d, J=4.9 Hz, 1H), 8.52 (d, J=4.0 Hz, 1H),7.82 (t, J=7.8 Hz, 1H), 7.72 (s, 1H), 7.67-7.62 (m, 3H), 7.56 (d, J=4.9Hz, 1H), 7.49-7.36 (m, 3H), 6.25 (s, 1H), 5.86 (d, J=10.1 Hz, 1H), 4.00(s, 3H), 2.68-2.59 (m, 1H), 2.30-2.21 (m, 1H), 2.14-2.03 (m, 1H),1.86-1.76 (m, 1H), 1.50-1.40 (m, 1H), 1.37-1.26 (m, 1H), 0.87 (d, J=7.0Hz, 3H), 0.52-0.33 (m, 1H). Analytical HPLC (Method C): RT=1.12 min,100% purity; Factor XIa Ki=350 nM.

Example 317 Preparation of(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-4-(2-methoxypyridin-3-yl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2,5,14,16-pentaen-8-one

(9R,13S)-13-(4-{5-Chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-4-(2-methoxypyridin-3-yl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2,5,14,16-pentaen-8-onewas prepared in a similar manner as the procedure described in Example216, by using 3-iodo-2-methoxypyridine (39 mg, 0.164 mmol) and(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(0.05 g, 0.082 mmol), as described in Example 196, to give(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-4-(2-methoxypyridin-3-yl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2,5,14,16-pentaen-8-onetrifluoroacetate (49 mg, 71% yield) as a light green solid. MS(ESI) m/z:717.5 (M+H)⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 9.47 (s, 1H), 9.24 (d, J=0.8Hz, 1H), 8.70 (s, 1H), 8.56 (d, J=5.0 Hz, 1H), 8.42 (s, 1H), 8.25 (dd,J=4.8, 1.8 Hz, 1H), 8.20 (dd, J=7.7, 1.7 Hz, 1H), 7.98 (d, J=2.2 Hz,1H), 7.91 (s, 1H), 7.89-7.81 (m, 2H), 7.58 (dd, J=5.1, 1.5 Hz, 1H), 7.24(dd, J=7.7, 4.7 Hz, 1H), 6.51 (s, 1H), 6.10-5.95 (m, 1H), 4.02 (s, 3H),2.84-2.70 (m, 1H), 2.35-2.18 (m, 2H), 1.91-1.75 (m, 1H), 1.63-1.50 (m,1H), 1.48-1.32 (m, 1H), 0.95 (d, J=7.2 Hz, 3H), 0.69-0.45 (m, 1H).Analytical HPLC (Method A): RT=10.02 min, purity=99.2%; Factor XIa Ki=18nM, Plasma Kallikrein Ki=850 nM.

Example 318 Preparation of(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(6-methoxypyrimidin-4-yl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

(9R,13S)-13-(4-{5-Chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(6-methoxypyrimidin-4-yl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate (0.83 mg, 0.908 μmol, 1% yield) as a minor product wasprepared in a similar manner as the procedure described in Example 216,by using 4-iodo-6-methoxypyrimidine (19.35 mg, 0.082 mmol) and(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(50 mg, 0.082 mmol), as described in Example 196. ¹H NMR (400 MHz,CD₃OD) δ 8.86 (s, 1H), 8.74 (s, 1H), 8.72 (s, 1H), 8.66 (d, J=5.3 Hz,1H), 8.59 (s, 1H), 8.07 (s, 1H), 7.95 (d, J=2.4 Hz, 1H), 7.80 (dd,J=8.5, 2.5 Hz, 2H), 7.76-7.70 (m, 1H), 7.45 (s, 1H), 6.50 (s, 1H), 5.93(d, J=9.0 Hz, 1H), 4.12 (s, 2H), 2.64 (s, 1H), 2.41 (s, 1H), 2.03 (s,2H), 1.72 (s, 1H), 1.46 (br. s., 2H), 1.34 (d, J=6.8 Hz, 3H), 1.24 (s,1H). MS(ESI) m/z: 718.3 [M+H]⁺. Analytical HPLC (Method A): RT=9.47 min,purity=91.0%; Factor XIa Ki=280 nM, Plasma Kallikrein Ki=5,200 nM.

Example 319 Preparation of(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-4-(6-methoxypyrimidin-4-yl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2,5,14,16-pentaen-8-one

(9R,13S)-13-(4-{5-Chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-4-(6-methoxypyrimidin-4-yl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2,5,14,16-pentaen-8-onetrifluoroacetate (5.5 mg, 6.28 μmol, 7% yield) as a major product wasprepared in a similar manner as the procedure described in Example 216,by using 4-iodo-6-methoxypyrimidine (19.35 mg, 0.082 mmol) and(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(50 mg, 0.082 mmol), as described in Example 196. ¹H NMR (400 MHz,CD₃OD) δ 8.86 (d, J=0.9 Hz, 1H), 8.79-8.73 (m, 1H), 8.71 (s, 2H), 8.67(d, J=5.1 Hz, 1H), 7.99-7.91 (m, 2H), 7.83-7.77 (m, 1H), 7.76-7.70 (m,2H), 7.43 (d, J=0.9 Hz, 1H), 6.49 (d, J=0.7 Hz, 1H), 6.15 (d, J=8.1 Hz,1H), 4.11 (s, 3H), 2.88 (d, J=3.3 Hz, 1H), 2.30 (t, J=12.7 Hz, 2H), 2.06(t, J=11.8 Hz, 1H), 1.82-1.68 (m, 1H), 1.60 (br. s., 1H), 1.10 (d, J=7.0Hz, 3H), 0.84 (br. s., 1H). MS(ESI) m/z: 718.3 [M+H]+. Analytical HPLC(Method A): RT=9.90 min, purity=95.0%; Factor XIa Ki=4 nM, PlasmaKallikrein Ki=100 nM.

Example 320 Preparation of(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-4-(6-hydroxypyrimidin-4-yl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2,5,14,16-pentaen-8-one

(9R,13S)-13-(4-{5-Chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-4-(6-hydroxypyrimidin-4-yl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2,5,14,16-pentaen-8-onetrifluoroacetate (5.4 mg, 6.47 μmol, 26% yield) was prepared in asimilar manner as the procedure described in Example 296. ¹H NMR (400MHz, CD₃OD) δ 8.85 (d, J=0.9 Hz, 1H), 8.73 (s, 1H), 8.67 (d, J=5.3 Hz,1H), 8.60 (s, 1H), 8.29 (d, J=0.9 Hz, 1H), 7.97 (s, 1H), 7.94 (d, J=2.4Hz, 1H), 7.81-7.76 (m, 1H), 7.76-7.69 (m, 2H), 7.00 (d, J=0.7 Hz, 1H),6.48 (s, 1H), 6.17-6.09 (m, 1H), 2.86 (d, J=3.5 Hz, 1H), 2.35-2.22 (m,2H), 2.12-1.99 (m, 1H), 1.81-1.53 (m, 3H), 1.09 (d, J=7.0 Hz, 3H), 0.86(br. s., 1H). MS(ESI) m/z: 704.5 [M+H]⁺. Analytical HPLC (Method A):RT=7.47 min, purity=98.0%; Factor XIa Ki=0.2 nM, Plasma Kallikrein Ki=39nM.

Example 321 Preparation of(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-4-(2-methoxypyridin-4-yl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2,5,14,16-pentaen-8-one

(9R,13S)-13-(4-{5-Chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-4-(2-methoxypyridin-4-yl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2,5,14,16-pentaen-8-one(4 mg, 6%) was prepared in a similar manner as the procedure describedin Example 216, by using 4-iodo-2-methoxypyridine (39 mg, 0.164 mmol)and(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(0.05 g, 0.082 mmol), as described in Example 196. MS(ESI) m/z: 717.1(M+H)⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 9.60 (s, 1H), 9.24 (s, 1H), 8.85 (s,1H), 8.71 (s, 1H), 8.60 (d, J=4.9 Hz, 1H), 8.31 (d, J=5.5 Hz, 1H), 7.98(s, 1H), 7.92 (s, 1H), 7.90-7.80 (m, 2H), 7.62 (dd, J=18.3, 4.9 Hz, 2H),7.36 (s, 1H), 6.51 (s, 1H), 6.03 (br. s., 1H), 3.94 (s, 3H), 3.46-3.27(m, 2H), 2.81 (br. s., 1H), 2.27 (d, J=18.9 Hz, 2H), 1.85 (br. s., 1H),1.57 (br. s., 1H), 1.42 (br. s., 1H), 0.95 (d, J=6.4 Hz, 3H), 0.54 (br.s., 1H). Analytical HPLC (Method C): RT=1.81 min, purity=100%; FactorXIa Ki=0.6 nM, Plasma Kallikrein Ki=17 nM.

Preparation of Examples 322 to 352

The following compounds were made in a parallel manner using thefollowing procedure: Reagents were weighed into BIOTAGE® 0.5-2 mLmicrowave vials. Stock solutions were made for reagent addition:Dissolved 472.9 mg core in 18.6 mL 1,4-dioxane (0.04M). Dissolved 265.7mg potassium carbonate in 6.2 mL water 0.3 M). To each microwave vialcontaining reagent was added Si-DPP-Pd (12.40 mg, 3.72 μmol) viaArgoScoop, 0.600 mL core solution, and 0.200 mL potassium carbonatesolution. Queued the reactions to run on the BIOTAGE® Initiator (400 W)microwave for 30 min at 120° C. with 10 seconds of prestirring and usinga fixed hold time.

Upon completion of the microwave run, reaction mixtures wereconcentrated, then redissolved in 1.8 mL DMF and filtered through a 45μM syringe filter. Resulting clear solutions were purified viapreparative LC/MS with the following conditions: Column: XBridge C18,19×100 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile: water with0.1% trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile: water with0.1% trifluoroacetic acid; Gradient: 40-80% B over 10 min, then a5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing thedesired product were combined and dried via centrifugal evaporation.Gradient varied for each reaction depending on polarity of compound.

Compound purity was assigned based on the methods below.

Method A: Column: Waters Acquity UPLC BEH C18, 2.1×50 mm, 1.7-μmparticles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammoniumacetate; Mobile Phase B: 95:5 acetonitrile:water with 10 mM ammoniumacetate; Temperature: 50° C.; Gradient: 0-100% B over 3 min, then a0.75-minute hold at 100% B; Flow: 1.11 mL/min; Detection: UV at 220 nm.

Method B: Column: Waters Acquity UPLC BEH C18, 2.1×50 mm, 1.7-μmparticles; Mobile Phase A: 5:95 acetonitrile:water with 0.1%trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with 0.1%trifluoroacetic acid; Temperature: 50° C.; Gradient: 0-100% B over 3min, then a 0.75-minute hold at 100% B; Flow: 1.11 mL/min; Detection: UVat 220 nm.

Example 322 Preparation of(9R,13S)-13-{4-[5-chloro-2-(4-methylphenyl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

MS(ESI) m/z: 579.1 (M+H)⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 9.14 (s, 1H),8.82 (s, 1H), 8.62 (d, J=5.2 Hz, 1H), 7.61 (d, J=2.4 Hz, 1H), 7.57 (s,1H), 7.53-7.49 (m, 2H), 7.40 (s, 1H), 7.34 (d, J=8.5 Hz, 1H), 7.10-7.03(m, 4H), 5.99 (s, 1H), 5.79 (d, J=10.1 Hz, 1H), 3.94 (s, 3H), 2.61-2.53(m, 1H), 2.26-2.17 (m, 4H), 2.07-1.99 (m, 1H), 1.80-1.72 (m, 1H),1.44-1.35 (m, 1H), 1.31-1.21 (m, 1H), 0.81 (d, J=6.7 Hz, 3H), 0.41-0.26(m, 1H). Analytical HPLC (Method A): RT=2.02 min, purity=98.7%; FactorXIa Ki=180 nM.

Example 323 Preparation of(9R,13S)-13-{4-[5-chloro-2-(3-chlorophenyl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

MS(ESI) m/z: 599.1 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 9.15 (s, 1H),8.76 (s, 1H), 8.60 (d, J=4.9 Hz, 1H), 7.63 (d, J=2.1 Hz, 1H), 7.59-7.54(m, 2H), 7.50 (dd, J=5.2, 0.9 Hz, 1H), 7.43-7.39 (m, 2H), 7.34-7.26 (m,2H), 7.23 (s, 1H), 7.09 (d, J=7.3 Hz, 1H), 6.16 (s, 1H), 5.79 (d, J=11.0Hz, 1H), 3.94 (s, 3H), 2.61-2.53 (m, 1H), 2.27-2.17 (m, 1H), 2.07-1.97(m, 1H), 1.80-1.70 (m, 1H), 1.44-1.34 (m, 1H), 1.31-1.20 (m, 1H), 0.81(d, J=6.7 Hz, 3H), 0.43-0.29 (m, 1H). Analytical HPLC (Method A):RT=2.03 min, purity=94.8%; Factor XIa Ki=7,500 nM.

Example 324 Preparation of(9R,13S)-13-{4-[5-chloro-2-(3-methoxyphenyl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

MS(ESI) m/z: 595.1 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 9.15 (s, 1H),8.81 (s, 1H), 8.61 (d, J=5.2 Hz, 1H), 7.61 (d, J=2.1 Hz, 1H), 7.58 (s,1H), 7.55-7.49 (m, 2H), 7.41-7.37 (m, 2H), 7.18 (t, J=7.9 Hz, 1H), 6.80(dd, J=8.2, 2.1 Hz, 1H), 6.73 (d, J=7.6 Hz, 1H), 6.69 (s, 1H), 6.04 (s,1H), 5.78 (d, J=10.1 Hz, 1H), 3.94 (s, 3H), 3.58 (s, 3H), 2.60-2.53 (m,1H), 2.27-2.18 (m, 1H), 2.07-1.98 (m, 1H), 1.81-1.71 (m, 1H), 1.44-1.34(m, 1H), 1.31-1.21 (m, 1H), 0.81 (d, J=6.7 Hz, 3H), 0.43-0.29 (m, 1H);Analytical HPLC (Method A): RT=1.91 min, purity=97.5%; Factor XIa Ki=550nM.

Example 325 Preparation of(9R,13S)-13-{4-[5-chloro-2-(2-methylphenyl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

MS(ESI) m/z: 579.1 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 9.20 (s, 1H),8.91 (s, 1H), 8.68 (d, J=5.2 Hz, 1H), 7.86 (d, J=2.4 Hz, 1H), 7.63-7.55(m, 3H), 7.46 (s, 1H), 7.31-7.18 (m, 4H), 7.11 (s, 1H), 5.85-5.78 (m,2H), 4.00 (d, J=3.1 Hz, 3H), 2.67-2.60 (m, 1H), 2.32-2.22 (m, 1H),2.13-2.03 (m, 1H), 1.95 (d, J=12.8 Hz, 3H), 1.86-1.76 (m, 1H), 1.49-1.39(m, 1H), 1.37-1.28 (m, 1H), 0.87 (d, J=6.7 Hz, 3H), 0.46-0.31 (m, 1H);Analytical HPLC (Method A): RT=2.05 min, purity=100%; Factor XIaKi=3,900.

Example 326 Preparation of(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethoxy)phenyl]phenyl)}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

MS(ESI) m/z: 649 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 9.21 (s, 1H), 8.83(s, 1H), 8.66 (d, J=4.9 Hz, 1H), 7.71 (d, J=2.1 Hz, 1H), 7.67-7.61 (m,2H), 7.59 (d, J=4.9 Hz, 1H), 7.51-7.46 (m, 2H), 7.38-7.30 (m, 4H), 6.22(s, 1H), 5.88 (d, J=10.4 Hz, 1H), 4.01 (s, 3H), 2.69-2.60 (m, 1H),2.32-2.23 (m, 1H), 2.16-2.06 (m, 1H), 1.86-1.77 (m, 1H), 1.52-1.42 (m,1H), 1.38-1.28 (m, 1H), 0.88 (d, J=7.0 Hz, 3H), 0.48-0.34 (m, 1H);Analytical HPLC (Method A): RT=2.14 min, purity=100%; Factor XIa Ki=640.

Example 327 Preparation of(9R,13S)-13-{4-[5-chloro-2-(2-chlorophenyl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

MS(ESI) m/z: 599 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 9.20 (s, 1H), 8.89(d, J=5.5 Hz, 1H), 8.70-8.66 (m, 1H), 7.85 (s, 1H), 7.66-7.61 (m, 2H),7.57 (d, J=4.6 Hz, 1H), 7.52-7.46 (m, 2H), 7.43-7.29 (m, 4H), 5.93, 5.91(2 s, 1H), 5.84 (d, J=11.0 Hz, 1H), 4.01, 4.00 (2 s, 3H), 2.66-2.60 (m,1H), 2.32-2.22 (m, 1H), 2.13-2.04 (m, 1H), 1.85-1.75 (m, 1H), 1.50-1.40(m, 1H), 1.37-1.27 (m, 1H), 0.87 (d, J=6.7 Hz, 3H), 0.45-0.31 (m, 1H);Analytical HPLC (Method A): RT=2.01 min, purity=100%; Factor XIaKi=3,300 nM.

Example 329 Preparation of(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)phenyl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

MS(ESI) m/z: 633.1 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 9.21 (s, 1H),8.82 (s, 1H), 8.64 (d, J=4.9 Hz, 1H), 7.74 (d, J=2.1 Hz, 1H), 7.71-7.64(m, 4H), 7.59 (d, J=4.9 Hz, 1H), 7.53-7.44 (m, 4H), 6.26 (s, 1H), 5.88(d, J=9.8 Hz, 1H), 4.01 (s, 3H), 2.68-2.59 (m, 1H), 2.32-2.24 (m, 1H),2.15-2.06 (m, 1H), 1.86-1.77 (m, 1H), 1.51-1.42 (m, 1H), 1.38-1.28 (m,1H), 0.88 (d, J=6.7 Hz, 3H), 0.48-0.32 (m, 1H); Analytical HPLC (MethodA): RT=2.09 min, purity=100%; Factor XIa Ki=380 nM.

Example 330 Preparation of(9R,13S)-13-(4-{5-chloro-2-[4-(propan-2-ylsulfanyl)phenyl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

MS(ESI) m/z: 639.1 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 9.15 (s, 1H),8.80 (s, 1H), 8.62 (d, J=5.2 Hz, 1H), 7.65 (d, J=2.1 Hz, 1H), 7.60 (s,1H), 7.57-7.52 (m, 2H), 7.43-7.38 (m, 2H), 7.25 (d, J=7.9 Hz, 2H), 7.12(d, J=8.2 Hz, 2H), 6.08 (s, 1H), 5.82 (d, J=9.8 Hz, 1H), 3.96 (s, 3H),3.49-3.39 (m, 1H), 2.62-2.55 (m, 1H), 2.27-2.17 (m, 1H), 2.10-2.01 (m,1H), 1.81-1.72 (m, 1H), 1.46-1.36 (m, 1H), 1.33-1.23 (m, 1H), 1.18 (dd,J=6.6, 2.0 Hz, 6H), 0.83 (d, J=7.0 Hz, 3H), 0.42-0.28 (m, 1H);Analytical HPLC (Method A): RT=2.25 min, purity=100%; Factor XIa Ki=400nM.

Example 331 Preparation of4-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)benzene-1-sulfonamide

MS(ESI) m/z: 644 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 9.21 (s, 1H), 8.85(s, 1H), 8.69 (d, J=5.2 Hz, 1H), 7.78 (d, J=8.2 Hz, 2H), 7.73 (d, J=2.1Hz, 1H), 7.67-7.64 (m, 2H), 7.58 (d, J=5.2 Hz, 1H), 7.52-7.40 (m, 6H),6.25 (s, 1H), 5.89 (d, J=10.7 Hz, 1H), 4.01 (s, 3H), 2.68-2.60 (m, 1H),2.33-2.24 (m, 1H), 2.15-2.06 (m, 1H), 1.88-1.78 (m, 1H), 1.51-1.42 (m,1H), 1.39-1.28 (m, 1H), 0.88 (d, J=6.7 Hz, 3H), 0.48-0.33 (m, 1H);Analytical HPLC (Method A): RT=1.54 min, purity=100%; Factor XIa Ki=130nM.

Example 332 Preparation of(9R,13S)-13-(4-{5-chloro-2-[4-(difluoromethoxy)phenyl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

MS(ESI) m/z: 631 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 9.21 (s, 1H), 8.86(s, 1H), 8.67 (d, J=4.9 Hz, 1H), 7.70 (d, J=2.1 Hz, 1H), 7.65 (s, 1H),7.63-7.57 (m, 2H), 7.49-7.42 (m, 2H), 7.31-7.26 (m, 3H), 7.17-7.11 (m,2H), 6.17 (s, 1H), 5.88 (d, J=9.8 Hz, 1H), 4.01 (s, 3H), 2.69-2.60 (m,1H), 2.34-2.24 (m, 1H), 2.16-2.06 (m, 1H), 1.88-1.79 (m, 1H), 1.51-1.42(m, 1H), 1.39-1.28 (m, 1H), 0.88 (d, J=6.7 Hz, 3H), 0.48-0.33 (m, 1H);Analytical HPLC (Method A): RT=1.97 min, purity=100%; Factor XIa Ki=180nM.

Example 333 Preparation ofN-[3-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)phenyl]methanesulfonamide

MS(ESI) m/z: 658 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 9.20 (s, 1H), 8.87(s, 1H), 8.69 (d, J=5.2 Hz, 1H), 7.70 (d, J=2.4 Hz, 1H), 7.66-7.60 (m,3H), 7.58 (d, J=5.2 Hz, 1H), 7.48-7.44 (m, 2H), 7.38-7.33 (m, 1H), 7.16(dd, J=8.1, 1.1 Hz, 1H), 7.06 (d, J=7.6 Hz, 1H), 7.03 (s, 1H), 6.10 (s,1H), 5.86 (d, J=9.8 Hz, 1H), 4.01 (s, 3H), 2.80 (s, 3H), 2.70-2.60 (m,1H), 2.34-2.24 (m, 1H), 2.15-2.05 (m, 1H), 1.88-1.78 (m, 1H), 1.51-1.42(m, 1H), 1.39-1.28 (m, 1H), 0.89 (d, J=7.0 Hz, 3H), 0.49-0.35 (m, 1H);Analytical HPLC (Method A): RT=1.68 min, purity=100%; Factor XIaKi=1,200 nM.

Example 334 Preparation of3-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)benzonitrile

MS(ESI) m/z: 590.3 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 9.21 (s, 1H),8.78 (s, 1H), 8.68 (d, J=5.2 Hz, 1H), 7.80 (dd, J=5.3, 2.3 Hz, 1H),7.74-7.70 (m, 2H), 7.68-7.64 (m, 2H), 7.59-7.51 (m, 4H), 7.47 (s, 1H),6.31 (s, 1H), 5.86 (d, J=10.4 Hz, 1H), 4.01 (s, 3H), 2.70-2.59 (m, 1H),2.33-2.23 (m, 1H), 2.14-2.04 (m, 1H), 1.86-1.77 (m, 1H), 1.51-1.41 (m,1H), 1.38-1.28 (m, 1H), 0.88 (d, J=7.0 Hz, 3H), 0.50-0.36 (m, 1H);Analytical HPLC (Method A): RT=1.8 min, purity=100%; Factor XIa Ki=1,600nM.

Example 335 Preparation of(9R,13S)-13-(4-{5-chloro-2-[3-(trifluoromethoxy)phenyl]phenyl)}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

MS(ESI) m/z: 649 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 9.20 (s, 1H), 8.84(s, 1H), 8.67 (d, J=5.2 Hz, 1H), 7.69 (d, J=2.1 Hz, 1H), 7.67-7.62 (m,2H), 7.58 (d, J=5.2 Hz, 1H), 7.52 (dt, J=8.1, 3.9 Hz, 2H), 7.47 (s, 1H),7.36 (d, J=7.9 Hz, 1H), 7.32 (d, J=8.2 Hz, 1H), 7.09 (s, 1H), 6.23 (s,1H), 5.88 (d, J=10.4 Hz, 1H), 4.00 (s, 3H), 2.69-2.60 (m, 1H), 2.33-2.24(m, 1H), 2.14-2.05 (m, 1H), 1.82-1.72 (m, 1H), 1.51-1.41 (m, 1H),1.37-1.27 (m, 1H), 0.88 (d, J=7.0 Hz, 3H), 0.49-0.36 (m, 1H); AnalyticalHPLC (Method A): RT=2.13 min, purity=100%; Factor XIa Ki=3,700 nM.

Example 336 Preparation of(9R,13S)-13-{4-[5-chloro-2-(3-methanesulfonylphenyl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

MS(ESI) m/z: 643 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 9.24, 9.21 (s, 1H),9.02, 8.79 (2 s, 1H), 8.71-8.63 (m, J=14.0, 4.9 Hz, 1H), 8.17-7.43 (m,9H), 7.07, 6.32 (2 s, 1H), 5.99-5.78 (m, 1H), 4.01 (d, J=1.8 Hz, 3H),3.91, 3.11 (2 s, 3H), 2.70-2.59 (m, 1H), 2.41-2.21 (m, 1H), 2.18-2.04(m, 1H), 1.99-1.75 (m, 1H), 1.54-1.26 (m, 2H), 0.93-0.85 (m, 3H),0.55-0.35 (m, 1H); Analytical HPLC (Method A): RT=1.65 min, purity=100%;Factor XIa Ki=1,200 nM.

Example 337 Preparation of methyl4-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)benzoate

MS(ESI) m/z: 623.1 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 9.14 (s, 1H),8.74 (s, 1H), 8.60 (d, J=4.9 Hz, 1H), 7.84 (d, J=8.2 Hz, 2H), 7.66 (d,J=2.1 Hz, 1H), 7.60-7.56 (m, 2H), 7.51 (d, J=5.2 Hz, 1H), 7.45-7.38 (m,2H), 7.31 (d, J=8.2 Hz, 2H), 6.12 (s, 1H), 5.82-5.75 (m, 1H), 3.94 (s,3H), 3.80 (s, 3H), 2.61-2.53 (m, 1H), 2.26-2.16 (m, 1H), 2.09-1.97 (m,1H), 1.80-1.71 (m, 1H), 1.44-1.19 (m, 2H), 0.81 (d, J=6.7 Hz, 3H),0.42-0.25 (m, 1H); Analytical HPLC (Method A): RT=1.91 min,purity=98.6%; Factor XIa Ki=750 nM.

Example 338 Preparation of(9R,13S)-13-{4-[5-chloro-2-(3-methylphenyl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

MS(ESI) m/z: 579.1 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 9.22 (s, 1H),8.86 (s, 1H), 8.68 (d, J=5.2 Hz, 1H), 7.68 (d, J=2.1 Hz, 1H), 7.65 (s,1H), 7.62-7.56 (m, 2H), 7.47 (s, 1H), 7.44 (d, J=8.5 Hz, 1H), 7.24-7.18(m, 1H), 7.13 (d, J=7.6 Hz, 1H), 7.05 (s, 1H), 7.00 (d, J=7.6 Hz, 1H),6.09 (s, 1H), 5.85 (d, J=10.4 Hz, 1H), 4.01 (s, 3H), 2.67-2.60 (m, 1H),2.35-2.22 (m, 4H), 2.14-2.05 (m, 1H), 1.88-1.78 (m, 1H), 1.51-1.42 (m,1H), 1.38-1.28 (m, 1H), 0.88 (d, J=7.0 Hz, 3H), 0.51-0.37 (m, 1H);Analytical HPLC (Method A): RT=2.03 min, purity=100%; Factor XIaKi=1,400 nM.

Example 339 Preparation of4-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)benzonitrile

MS(ESI) m/z: 590.1 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 9.22 (s, 1H),8.79 (s, 1H), 8.67 (d, J=4.9 Hz, 1H), 7.80 (d, J=8.2 Hz, 2H), 7.73 (d,J=2.1 Hz, 1H), 7.69-7.64 (m, 2H), 7.59 (d, J=5.2 Hz, 1H), 7.50 (d, J=8.2Hz, 1H), 7.47 (s, 1H), 7.43 (d, J=8.5 Hz, 2H), 6.29 (s, 1H), 5.87 (d,J=10.1 Hz, 1H), 4.01 (s, 3H), 2.69-2.60 (m, 1H), 2.33-2.23 (m, 1H),2.15-2.06 (m, 1H), 1.87-1.78 (m, 1H), 1.52-1.42 (m, 1H), 1.38-1.28 (m,1H), 0.88 (d, J=6.7 Hz, 3H), 0.49-0.33 (m, 1H); Analytical HPLC (MethodA): RT=1.8 min, purity=100%; Factor XIa Ki=290 nM.

Example 340 Preparation of(9R,13S)-13-{4-[5-chloro-2-(1-methyl-1H-indol-5-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

MS(ESI) m/z: 618.1 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 9.20 (s, 1H),8.90 (s, 1H), 8.68 (d, J=5.2 Hz, 1H), 7.72 (d, J=2.1 Hz, 1H), 7.61 (s,1H), 7.60-7.55 (m, 2H), 7.47-7.43 (m, 3H), 7.39-7.33 (m, 2H), 6.96 (dd,J=8.5, 1.2 Hz, 1H), 6.40 (d, J=3.1 Hz, 1H), 5.98 (s, 1H), 5.82 (d,J=10.7 Hz, 1H), 4.00 (s, 3H), 3.79 (s, 3H), 2.66-2.59 (m, 1H), 2.33-2.24(m, 1H), 2.13-2.03 (m, 1H), 1.85-1.77 (m, 1H), 1.49-1.40 (m, 1H),1.37-1.27 (m, 1H), 0.87 (d, J=7.0 Hz, 3H), 0.45-0.32 (m, 1H); AnalyticalHPLC (Method A): RT=2.02 min, purity=100%; Factor XIa Ki=1,300 nM.

Example 341 Preparation of(9R,13S)-13-{4-[5-chloro-2-(isoquinolin-5-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

MS(ESI) m/z: 616 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 9.48 (d, J=16.8 Hz,1H), 9.17 (s, 1H), 8.66-8.58 (m, 2H), 8.43 (br. s., 1H), 8.24 (t, J=9.3Hz, 1H), 7.90 (t, J=1.8 Hz, 1H), 7.82-7.69 (m, 3H), 7.56-7.51 (m, 2H),7.48 (dd, J=8.2, 3.4 Hz, 1H), 7.45-7.38 (m, 2H), 6.00 (d, J=9.5 Hz, 1H),5.69 (d, J=10.4 Hz, 1H), 3.99 (s, 3H), 2.63-2.57 (m, 1H), 2.19-1.96 (m,2H), 1.73-1.59 (m, 1H), 1.45-1.34 (m, 1H), 1.31-1.20 (m, 1H), 0.85 (d,J=5.2 Hz, 3H), 0.41-0.28 (m, 1H); Analytical HPLC (Method B): RT=1.32min, purity=100%; Factor XIa Ki=6,500 nM.

Example 342 Preparation of methyl3-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)benzoate

MS(ESI) m/z: 623.2 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 9.21 (s, 1H),8.80 (s, 1H), 8.65 (d, J=5.2 Hz, 1H), 7.93-7.89 (m, 1H), 7.79 (s, 1H),7.71 (d, J=2.1 Hz, 1H), 7.66-7.63 (m, 2H), 7.58 (d, J=5.2 Hz, 1H),7.54-7.46 (m, 4H), 6.23 (s, 1H), 5.86 (d, J=9.8 Hz, 1H), 4.01 (s, 3H),3.78 (s, 3H), 2.67-2.59 (m, 1H), 2.31-2.22 (m, 1H), 2.14-2.05 (m, 1H),1.83-1.74 (m, 1H), 1.51-1.41 (m, 1H), 1.37-1.27 (m, 1H), 0.88 (d, J=7.0Hz, 3H), 0.50-0.36 (m, 1H); Analytical HPLC (Method A): RT=1.87 min,purity=100%; Factor XIa Ki=2,200 nM.

Example 343 Preparation ofN-[4-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)phenyl]methanesulfonamide

MS(ESI) m/z: 657.9 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 9.21 (s, 1H),8.86 (s, 1H), 8.70 (d, J=5.2 Hz, 1H), 7.70 (d, J=2.4 Hz, 1H), 7.65 (s,1H), 7.62-7.56 (m, 2H), 7.50-7.42 (m, 2H), 7.30-7.25 (m, 1H), 7.22-7.14(m, 4H), 6.11 (s, 1H), 5.86 (d, J=8.9 Hz, 1H), 4.01 (s, 3H), 2.99 (s,3H), 2.68-2.61 (m, 1H), 2.34-2.23 (m, 1H), 2.16-2.06 (m, 1H), 1.88-1.78(m, 1H), 1.53-1.28 (m, 2H), 0.88 (d, J=7.0 Hz, 3H), 0.51-0.33 (m, 1H);Analytical HPLC (Method B): RT=1.63 min, purity=97.8%; Factor XIa Ki=450nM.

Example 344 Preparation of(9R,13S)-13-(4-{5-chloro-2-[3-(trifluoromethyl)phenyl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

MS(ESI) m/z: 633 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 9.21 (s, 1H), 8.79(s, 1H), 8.65 (d, J=5.2 Hz, 1H), 7.73-7.64 (m, 4H), 7.61-7.54 (m, 4H),7.52-7.46 (m, 2H), 6.30 (s, 1H), 5.86 (d, J=10.4 Hz, 1H), 4.01 (s, 3H),2.67-2.59 (m, 1H), 2.33-2.23 (m, 1H), 2.14-2.05 (m, J=12.1, 12.1 Hz,1H), 1.82-1.73 (m, 1H), 1.50-1.41 (m, 1H), 1.37-1.27 (m, 1H), 0.88 (d,J=6.7 Hz, 3H), 0.52-0.38 (m, 1H); Analytical HPLC (Method A): RT=2.06min, purity=100%; Factor XIa Ki=4,800 nM.

Example 345 Preparation of(9R,13S)-13-{4-[5-chloro-2-(4-methoxyphenyl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

MS(ESI) m/z: 595 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 9.22 (s, 1H), 8.89(s, 1H), 8.69 (d, J=5.2 Hz, 1H), 7.68-7.64 (m, 2H), 7.60-7.56 (m, 2H),7.47 (s, 1H), 7.41 (d, J=8.2 Hz, 1H), 7.15 (d, J=8.5 Hz, 2H), 6.90 (d,J=8.9 Hz, 2H), 6.08 (s, 1H), 5.87 (d, J=10.1 Hz, 1H), 4.01 (s, 3H), 3.76(s, 3H), 2.68-2.60 (m, 1H), 2.34-2.26 (m, 1H), 2.16-2.06 (m, 1H),1.89-1.79 (m, 1H), 1.51-1.42 (m, 1H), 1.39-1.28 (m, 1H), 0.88 (d, J=7.0Hz, 3H), 0.48-0.35 (m, 1H); Analytical HPLC (Method A): RT=1.89 min,purity=100%; Factor XIa Ki=350 nM.

Example 346 Preparation of(9R,13S)-13-{4-[5-chloro-2-(4-chlorophenyl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

MS(ESI) m/z: 599 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 9.22 (s, 1H), 8.85(s, 1H), 8.68 (d, J=4.9 Hz, 1H), 7.70 (d, J=2.1 Hz, 1H), 7.66 (s, 1H),7.63 (dd, J=8.2, 2.1 Hz, 1H), 7.59 (d, J=5.2 Hz, 1H), 7.48-7.44 (m, 2H),7.40 (d, J=8.5 Hz, 2H), 7.25 (d, J=8.2 Hz, 2H), 6.19 (s, 1H), 5.88 (d,J=9.8 Hz, 1H), 4.01 (s, 3H), 2.69-2.60 (m, 1H), 2.34-2.25 (m, 1H),2.15-2.06 (m, 1H), 1.88-1.79 (m, 1H), 1.52-1.42 (m, 1H), 1.39-1.28 (m,1H), 0.88 (d, J=6.7 Hz, 3H), 0.49-0.34 (m, 1H); Analytical HPLC (MethodB): RT=2 min, purity=95.5%; Factor XIa Ki=220 nM.

Example 347 Preparation of(9R,13S)-13-{4-[5-chloro-2-(pyridin-4-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

MS(ESI) m/z: 566.1 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 9.21 (s, 1H),8.80 (s, 1H), 8.68 (d, J=5.2 Hz, 1H), 8.55 (d, J=5.8 Hz, 2H), 7.74 (d,J=1.8 Hz, 1H), 7.69 (dd, J=8.2, 2.1 Hz, 1H), 7.66 (s, 1H), 7.58 (d,J=5.2 Hz, 1H), 7.53 (d, J=8.2 Hz, 1H), 7.47 (s, 1H), 7.30 (d, J=5.8 Hz,2H), 6.34 (s, 1H), 5.87 (d, J=10.7 Hz, 1H), 4.01 (s, 3H), 2.69-2.60 (m,1H), 2.33-2.23 (m, 1H), 2.15-2.06 (m, 1H), 1.88-1.78 (m, 1H), 1.52-1.42(m, 1H), 1.38-1.28 (m, 1H), 0.88 (d, J=7.0 Hz, 3H), 0.48-0.35 (m, 1H);Analytical HPLC (Method A): RT=1.52 min, purity=98.9%; Factor XIaKi=2,000 nM.

Example 348 Preparation of(9R,13S)-13-{4-[5-chloro-2-(isoquinolin-7-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

MS(ESI) m/z: 616 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 9.25 (d, J=7.3 Hz,2H), 8.73 (s, 1H), 8.60 (d, J=5.2 Hz, 1H), 8.50 (d, J=5.8 Hz, 1H), 8.03(s, 1H), 7.90 (d, J=8.5 Hz, 1H), 7.86 (d, J=5.5 Hz, 1H), 7.75 (d, J=1.8Hz, 1H), 7.70-7.66 (m, 1H), 7.63-7.56 (m, 3H), 7.53 (d, J=4.9 Hz, 1H),7.45 (s, 1H), 6.22 (s, 1H), 5.82-5.74 (m, 1H), 3.98 (s, 3H), 2.66-2.59(m, 1H), 2.25-2.16 (m, 1H), 2.07-1.99 (m, 1H), 1.83-1.74 (m, 1H),1.48-1.38 (m, 1H), 1.35-1.25 (m, 1H), 0.85 (d, J=7.0 Hz, 3H), 0.47-0.32(m, 1H); Analytical HPLC (Method A): RT=1.77 min, purity=94.8%; FactorXIa Ki=260 nM, Plasma Kallikrein Ki=3,600 nM.

Example 349 Preparation of(9R,13S)-13-{4-[5-chloro-2-(pyrimidin-5-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

MS(ESI) m/z: 567 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 9.22 (s, 1H), 9.16(s, 1H), 8.80 (s, 1H), 8.71-8.66 (m, 3H), 7.79 (d, J=2.1 Hz, 1H), 7.73(dd, J=8.2, 1.8 Hz, 1H), 7.67 (s, 1H), 7.62 (d, J=8.2 Hz, 1H), 7.58 (d,J=4.9 Hz, 1H), 7.48 (s, 1H), 6.46 (s, 1H), 5.89 (d, J=10.4 Hz, 1H), 4.02(s, 3H), 2.69-2.61 (m, 1H), 2.33-2.23 (m, 1H), 2.16-2.07 (m, J=13.7 Hz,1H), 1.87-1.78 (m, 1H), 1.52-1.43 (m, 1H), 1.38-1.28 (m, 1H), 0.89 (d,J=6.7 Hz, 3H), 0.48-0.35 (m, 1H); Analytical HPLC (Method A): RT=1.4min, purity=100%; Factor XIa Ki=16 nM, Plasma Kallikrein Ki=3,000 nM.

Example 350 Preparation of ethyl2-[4-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)-1H-pyrazol-1-yl]acetate

MS(ESI) m/z: 631.1 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 9.25 (s, 1H),8.84 (s, 1H), 8.67 (d, J=5.2 Hz, 1H), 7.69 (d, J=1.8 Hz, 1H), 7.66-7.46(m, 6H), 7.43-7.38 (m, 1H), 7.16-7.11 (m, 2H), 7.00 (br. s., 1H), 6.20(s, 1H), 5.89-5.82 (m, 1H), 4.01 (s, 3H), 2.68-2.60 (m, 1H), 2.33-2.23(m, 1H), 2.13-2.04 (m, J=7.0 Hz, 1H), 1.86-1.77 (m, 1H), 1.52-1.42 (m,1H), 1.38-1.28 (m, 1H), 0.89 (d, J=6.7 Hz, 3H), 0.51-0.37 (m, 1H);Analytical HPLC (Method A): RT=1.99 min, purity=96.9%; Factor XIa Ki=600nM.

Example 351 Preparation of(9R,13S)-13-{4-[5-chloro-2-(1-ethyl-1H-pyrazol-4-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

MS(ESI) m/z: 583.1 (M+H)⁺; ¹H NMR (400 MHz, CD₃OD) δ 8.98 (s, 1H), 8.75(d, J=5.1 Hz, 1H), 7.72 (s, 1H), 7.60 (s, 1H), 7.56-7.52 (m, 2H), 7.49(s, 1H), 7.48-7.47 (m, 2H), 7.36 (s, 1H), 6.39 (s, 1H), 6.02 (dd,J=12.7, 4.3 Hz, 1H), 4.12 (q, J=7.3 Hz, 2H), 4.05 (s, 3H), 2.76-2.67 (m,1H), 2.39-2.29 (m, 1H), 2.14-2.00 (m, 2H), 1.67-1.43 (m, 2H), 1.37 (t,J=7.3 Hz, 3H), 1.01 (d, J=6.8 Hz, 3H), 0.79-0.64 (m, 1H); AnalyticalHPLC (Method A): RT=1.55 min, purity=95.5%; Factor XIa Ki=96 nM.

Example 352 Preparation of(9R,13S)-13-(4-{5-chloro-2-[1-(4-fluorophenyl)-1H-pyrazol-4-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

MS(ESI) m/z: 649.3 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 9.24 (s, 1H),8.95 (s, 1H), 8.62 (d, J=5.2 Hz, 1H), 8.53 (s, 1H), 7.83 (dd, J=8.9, 4.6Hz, 2H), 7.70 (s, 1H), 7.67-7.56 (m, 5H), 7.49 (s, 1H), 7.36 (t, J=8.7Hz, 2H), 6.46 (s, 1H), 5.96 (d, J=10.7 Hz, 1H), 4.03 (s, 3H), 2.70-2.62(m, 1H), 2.38-2.28 (m, 1H), 2.18-2.10 (m, 1H), 1.94-1.85 (m, 1H),1.54-1.45 (m, 1H), 1.41-1.31 (m, 1H), 0.90 (d, J=6.7 Hz, 3H), 0.51-0.38(m, 1H); Analytical HPLC (Method A): RT=1.99 min, purity=100%; FactorXIa Ki=7 nM.

Example 353 Preparation of(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate

353A. Preparation of 1-(difluoromethyl)-4-nitro-1H-pyrazole Cs₂CO₃(14.41 g, 44.2 mmol) was suspended in a solution of 4-nitro-1H-pyrazole(5.00 g, 44.2 mmol) and DMF (40 mL). After heating to 120° C. for 5 min,solid sodium 2-chloro-2,2-difluoroacetate (13.48 g, 88 mmol) was addedin 10 equal portions over 20 min. The reaction was complete after 10 minof additional heating. The mixture was added to a separatory funnelcontaining 100 mL water and extracted with Et₂O (2×50 mL). The combinedorganic layers were concentrated. Purification by normal-phasechromatography eluting with a gradient of hexanes/EtOAc yielded1-(difluoromethyl)-4-nitro-1H-pyrazole (6.99 g, 42.9 mmol, 97% yield) asa clear, colorless oil. ¹H NMR (500 MHz, CDCl₃) δ 8.58 (s, 1H), 8.22 (s,1H), 7.39-7.05 (t, J=60 Hz, 1H).

353B. Preparation of (S)-tert-butyl(1-(4-(1-(difluoromethyl)-4-nitro-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate

To a N₂ flushed, 500 mL RBF was added (S)-tert-butyl(1-(4-chloropyridin-2-yl)but-3-en-1-yl)carbamate, prepared as describedin Example 355, (10 g, 35.4 mmol), 1-(difluoromethyl)-4-nitro-1H-pyrazol(6.34 g, 38.9 mmol) and dioxane (100 mL). The solution was bubbled withN₂ for 5 min. Then Pd(OAc)₂ (0.40 g, 1.7 mmol),di(adamantan-1-yl)(butyl)phosphine (1.27 g, 3.5 mmol), K₂CO₃ (14.7 g,106 mmol) and PvOH (1.08 g, 10.61 mmol) were added. The reaction mixturewas bubbled with N₂ for 5 min then the reaction mixture was heated to100° C. for 3 h. After this time, the solution was cooled to rt andwater (200 mL) was added. The reaction mixture was then extracted withEtOAc (2×200 mL). The combined organic extracts were washed with water(200 mL), brine (200 mL), dried over Na₂SO₄, filtered and concentratedin vacuo. Purification by normal phase chromatography eluting with agradient of hexanes/EtOAc afforded (S)-tert-butyl(1-(4-(1-(difluoromethyl)-4-nitro-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate(12.91 g, 31.5 mmol, 89% yield) as a slightly yellow oil. MS(ESI) m/z:410.4 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.80 (dd, J=5.1, 0.7 Hz, 1H),8.36 (s, 1H), 7.34 (s, 1H), 7.31 (dd, J=5.1, 1.5 Hz, 1H), 7.27-6.91 (t,J=58 Hz, 1H), 5.79-5.63 (m, 1H), 5.16-5.03 (m, 2H), 4.92 (d, J=5.9 Hz,1H), 2.67 (t, J=6.4 Hz, 2H), 1.46 (br. s., 9H).

353C. Preparation of (S)-tert-butyl(1-(4-(4-amino-1-(difluoromethyl)-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate

To a 100 mL, 3-necked RBF was added a solution of (S)-tert-butyl(1-(4-(1-(difluoromethyl)-4-nitro-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate(0.78 g, 1.90 mmol) in MeOH (12 mL) and a solution of NH₄Cl (1.02 g, 19mmol) in water (3 mL). To the solution was added Fe (0.53 g, 9.49 mmol).The reaction mixture was heated to 65° C. for 3 h. Water (50 mL) wasadded. After cooling to rt, the mixture was filtered through a CELITE®pad and rinsed with MeOH (200 mL). The filtrate was concentrated invacuo. The residue was partitioned between EtOAC (100 mL) and water (100mL). The organic phase was separated, washed with water (100 mL), brine(100 mL), dried over Na₂SO₄, filtered and concentrated in vacuo.Purification by normal phase chromatography eluting with a gradient ofDCM/MeOH yielded (S)-tert-butyl(1-(4-(4-amino-1-(difluoromethyl)-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate(0.585 g, 1.54 mmol, 81% yield) as an oil. MS(ESI) m/z: 380.1 [M+H]⁺. ¹HNMR (400 MHz, CDCl₃) δ 8.70 (dd, J=5.0, 0.7 Hz, 1H), 7.43 (s, 1H), 7.36(s, 1H), 7.32 (dd, J=5.1, 1.5 Hz, 1H), 7.28-6.97 (t, J=58 Hz, 1H),5.80-5.66 (m, 1H), 5.65-5.53 (m, 1H), 5.13-5.03 (m, 2H), 4.87 (br. s.,1H), 3.22 (br. s., 2H), 2.65 (t, J=6.5 Hz, 2H), 1.52-1.37 (m, 9H).

353D. Preparation of tert-butyl((S)-1-(4-(1-(difluoromethyl)-4-((R)-2-methylbut-3-enamido)-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate

To a N₂ flushed, 3-necked, 250 mL RBF was added a solution of(S)-tert-butyl(1-(4-(4-amino-1-(difluoromethyl)-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate(5 g, 13.18 mmol) and EtOAc (50 ml). The solution was cooled to −10° C.and (R)-2-methylbut-3-enoic acid, as prepared in Example 354, (1.72 g,17.13 mmol), pyridine (4.26 ml, 52.7 mmol). and T3P® (23.54 ml, 39.5mmol) were added. The cooling bath was removed and the solution wasallowed to warm to rt and then stir over a period of 20 h. Water (30 mL)and EtOAc (30 mL) were added and the mixture was stirred for 30 min. Theorganic phase was separated and the aqueous layer was extracted withEtOAc (30 mL). The combined organic extracts were washed with brine (50mL), dried over Na₂SO₄, filtered and concentrated in vacuo. Purificationby normal phase chromatography eluting with a gradient of hexanes/EtOAcgave tert-butyl((S)-1-(4-(1-(difluoromethyl)-4-((R)-2-methylbut-3-enamido)-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate(5.69 g, 12.33 mmol, 94% yield). MS(ESI) m/z: 462.2 [M+H]⁺. ¹H NMR (400MHz, CDCl₃) δ 8.75 (dd, J=5.0, 0.6 Hz, 1H), 8.37 (s, 1H), 7.32 (t, J=59Hz, 1H), 7.28 (br. s., 1H), 7.20 (s, 1H), 5.97-5.85 (m, 1H), 5.78-5.65(m, 1H), 5.56-5.44 (m, 1H), 5.28-5.19 (m, 2H), 5.12 (d, J=2.0 Hz, 2H),4.91-4.82 (m, 1H), 3.20-3.11 (m, 1H), 2.72-2.62 (m, 2H), 1.48-1.43 (s,9H), 1.33 (d, J=6.8 Hz, 3H).

353E. Preparation of tert-butylN-[(9R,10E,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate

To a N₂ flushed, 2 L, 3-necked, RBF was added a solution of tert-butyl((S)-1-(4-(1-(difluoromethyl)-4-((R)-2-methylbut-3-enamido)-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate(3 g, 6.50 mmol) in EtOAc (1300 ml). The solution was sparged with argonfor 15 min. Grubbs II (1.38 g, 1.63 mmol) was added in one portion. Thereaction mixture was heated to reflux for 24 h. After cooling to rt, thesolvent was removed and the residue was purified by normal phasechromatography eluting with a gradient of DCM/MeOH to yield tert-butylN-[(9R,10E,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate(2.13 g, 4.91 mmol, 76% yield) as a tan solid. MS(ESI) m/z: 434.4[M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.71 (d, J=5.1 Hz, 1H), 7.78 (s, 1H),7.44-7.40 (m, 1H), 7.36 (br. s., 1H), 7.27 (t, J=58 Hz, 1H), 6.87 (s,1H), 6.49-6.39 (m, 1H), 5.78 (s, 1H), 4.80 (br. s., 2H), 3.18-3.08 (m,1H), 3.08-2.98 (m, 1H), 2.06-1.93 (m, 1H), 1.51 (s, 9H), 1.19 (d, J=6.6Hz, 3H).

353F. Preparation of tert-butylN-[(9R,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate

Pd/C (0.60 g, 0.570 mmol) was added to a 250 mL Parr hydrogenation flaskcontaining a solution of tert-butylN-[(9R,10E,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate(2.46 g, 5.68 mmol) in EtOH (100 mL). The flask was purged with N₂ andpressurized to 55 psi of H₂ allowed to stir for 18 h. The reaction wasfiltered through CELITE® and concentrated to yield tert-butylN-[(9R,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate(2.17 g, 88% yield) as a tan solid. MS(ESI) m/z: 436.3 [M+H]⁺. ¹H NMR(400 MHz, DMSO-d₆) δ 9.32 (s, 1H), 8.71 (d, J=5.0 Hz, 1H), 7.96 (t, J=58Hz, 1H), 7.43 (s, 1H), 7.32 (d, J=4.8 Hz, 1H), 7.22 (d, J=7.3 Hz, 1H),4.66 (d, J=8.3 Hz, 1H), 2.62 (br. s., 1H), 1.88 (d, J=12.8 Hz, 1H),1.77-1.59 (m, 2H), 1.42-1.28 (m, 9H), 1.15 (d, J=18.2 Hz, 2H), 0.83 (d,J=7.0 Hz, 3H).

353G. Preparation of(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

4 N HCl in dioxane (3.88 mL, 15.5 mmol) was added to a solution oftert-butylN-[(9R,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate(2.25 g, 5.2 mmol) in MeOH (10 mL). The reaction was allowed to stir atrt for 2 h. The reaction was cooled in an ice bath, and 7 N NH₃ in MeOH(13.3 mL, 93.0 mmol) was added. After 5 min, the reaction was dilutedwith CH₂Cl₂ (80 mL) and the solid that formed was filtered. The filtratewas concentrated to yield(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(1.3 g, 3.88 mmol, 75% yield). MS(ESI) m/z: 336.3 [M+H]⁺. ¹H NMR (400MHz, DMSO-d₆) δ 9.33 (s, 1H), 8.71 (d, J=5.0 Hz, 1H), 7.94 (t, J=58 Hz,1H), 7.85 (s, 1H), 7.40 (s, 1H), 7.32 (d, J=5.0 Hz, 1H), 4.01 (dd,J=10.2, 5.1 Hz, 1H), 2.63-2.53 (m, 1H), 1.90-1.69 (m, 2H), 1.53-1.36 (m,2H), 1.16-1.00 (m, 1H), 0.85 (d, J=7.0 Hz, 3H).

353H. Preparation of(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

To a 100 mL flask containing a white suspension of6-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol(0.83 g, 2.7 mmol), as prepared in Example 356 in ACN (36 mL) was addedHATU (1.12 g, 3.0 mmol) and DBU (0.53 mL, 3.5 mmol). The resultingclear, yellow solution was stirred at rt. After 5 min,(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(0.9 g, 2.68 mmol) was added and the resulting suspension was stirred atrt for 3 h. The reaction was then concentrated and purified by normalphase silica gel chromatography, eluting with a gradient of 0% to 100%EtOAc in hexanes to yield(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(0.87 g, 50% yield) as a white solid. MS(ESI) m/z: 626.2 [M+H]⁺. ¹H NMR(500 MHz, CD₃OD) δ 8.91-8.83 (m, 1H), 8.78-8.71 (m, 1H), 8.33 (s, 1H),7.88 (d, J=2.5 Hz, 1H), 7.74 (s, 2H), 7.69-7.67 (m, 1H), 7.65 (s, 1H),7.63 (t, J=58 Hz, 1H), 7.52-7.50 (m, 1H), 6.36 (d, J=0.8 Hz, 1H),6.06-5.95 (m, 1H), 2.76-2.65 (m, 1H), 2.36-2.21 (m, 1H), 2.08-1.93 (m,2H), 1.63-1.53 (m, 1H), 1.53-1.42 (m, 1H), 0.99 (d, J=6.9 Hz, 3H).Analytical HPLC (Method A): RT=8.87 min, purity=99.7%.

Example 354

Preparation(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-4-(pyridin-3-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2,5,14,16-pentaen-8-onetrifluoroacetate

354A. Preparation of4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole

To a solution of 4-nitro-1H-pyrazole (5.0 g, 44.2 mmol) in THF (100 mL)at 0° C. was added N-cyclohexyl-N-methylcyclohexanamine (0.948 mL, 4.43mmol) followed by dropwise addition of SEM-Cl (12.55 mL, 70.7 mmol). Thereaction mixture was then allowed to gradually rise to rt and stirred atrt overnight. The reaction mixture was then concentrated, followed bypurification using normal phase chromatography to yield4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole as clear oil(2.4 g, 21% yield). ¹H NMR (500 MHz, CDCl₃) δ 8.31 (s, 1H), 8.10 (s,1H), 5.46 (s, 2H), 3.67-3.55 (m, 2H), 0.99-0.90 (m, 2H), 0.05-0.03 (m,9H).

354B. Preparation of (S)-benzyl(1-(4-(4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate

To a N₂ flushed pressure vial was added (S)-benzyl(1-(4-chloropyridin-2-yl)but-3-en-1-yl)carbamate, prepared as describedin Example 357, (1.9 g, 6.00 mmol),4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (1.6 g, 6.60mmol), di(adamant-1-yl)(butyl)phosphine (0.323 g, 0.90 mmol), PvOH(0.209 mL, 1.80 mmol) and K₂C₀₃ (2.48 g, 17.9 mmol). To the abovemixture was then added DMA (45 mL) and the vial was purged with N₂ for 5min. To this mixture was then added Pd(OAc)₂ (0.135 g, 0.600 mmol). Thereaction mixture was again briefly purged with N₂. The vial was sealedand heated in microwave at 120° C. for 1 h. The reaction mixture wascooled to rt and partitioned between 10% aqueous LiCl (15 mL) and EtOAc(30 mL). The aqueous layer was extracted with EtOAc (2×20 mL) and thecombined organic layers were washed with brine (15 mL) and dried overMgSO₄. The crude product was then purified using normal phasechromatography to yield (S)-benzyl (1-(4-(4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate(1.92 g, 58% yield) as a brown oil. MS(ESI) m/z: 524.2 (M+H)⁺.

354C. Preparation of (S)-benzyl(1-(4-(4-amino-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate

A solution of (S)-benzyl(1-(4-(4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate(1.92 g, 3.68 mmol), prepared as described in Example 354B, in MeOH (20mL) and AcOH (2 mL) was heated in oil bath to 40° C. To the above clearsolution was then slowly added Zn (0.481 g, 7.35 mmol, in 3 portions(50:25:25%)) and allowed to stir at the same temperature for 5 min.Additional Zn was added to the reaction. The reaction mixture wasmonitored by LCMS and when complete, the reaction mixture was cooled andthen 2.0 g of K₂CO₃ (1 g for 1 mL AcOH) and 2.0 mL water was added. Thereaction mixture was then stirred for 5 min. The reaction mixture wasthen filtered over a pad of CELITE® and concentrated in vacuo to yieldthe crude product. The crude product was then partitioned between EtOAc(30 mL) and saturated NaHCO₃ (15 mL) solution. The organic layers wereseparated, dried over MgSO₄, filtered and concentrated. The crudeproduct was then purified using normal phase chromatography to yield(S)-benzyl (1-(4-(4-amino-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate (1.15 g,63% yield) as pale yellow oil. MS(ESI) m/z: 494.4 (M+H)⁺.

354D. Preparation of benzyl((S)-1-(4-(4-((R)-2-methylbut-3-enamido)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate

To a N₂ flushed, 3-necked, 250 mL RBF was added a solution (S)-benzyl(1-(4-(4-amino-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate(1.15 g, 2.33 mmol) and EtOAc (15 mL). The solution was cooled to −10°C. and (R)-2-methylbut-3-enoic acid (350 mg, 3.49 mmol), pyridine (0.564mL, 6.99 mmol) and T3P® (2.77 mL, 4.66 mmol) were added. The coolingbath was removed and the solution was allowed to warm to rt and thenstir over a period of 20 h. Water (20 mL) and EtOAc (20 mL) were addedand the mixture was stirred for 30 min. The organic phase was separatedand the aqueous layer was extracted with EtOAc (20 mL). The combinedorganic extracts were washed with brine (15 mL), dried over Na₂SO₄,filtered and concentrated in vacuo. Purification by normal phasechromatography eluting with a gradient of hexanes/EtOAc gave benzyl((S)-1-(4-(4-((R)-2-methylbut-3-enamido)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate(1.12 g, 79% yield). MS(ESI) m/z: 576.4 [M+H]⁺.

354E. Preparation of benzylN-[(9R,10E,13S)-9-methyl-8-oxo-3-{[2-(trimethylsilyl)ethoxy]methyl}-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate

To a N₂ flushed, 250 mL, 3-necked, RBF was added a solution of benzyl((S)-1-(4-(4-((R)-2-methylbut-3-enamido)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate(1.12 g, 1.945 mmol) in DCE (18 mL). The solution was sparged with Arfor 15 min. Grubbs II (662 mg, 0.778 mmol) was added in one portion. Thereaction mixture was heated at 120° C. in microwave for 30 min. Aftercooling to rt, the solvent was removed and the residue was purified bynormal phase chromatography eluting with a gradient of DCM/MeOH to yieldbenzylN-[(9R,10E,13S)-9-methyl-8-oxo-3-{[2-(trimethylsilyl)ethoxy]methyl}-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate(477 mg, 42% yield) as a tan solid. MS(ESI) m/z: 548.3 [M+H]⁺.

354F. Preparation of benzylN-[(9R,13S)-9-methyl-8-oxo-3-{[2-(trimethylsilyl)ethoxy]methyl}-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate

Pd/C (0.93 g, 0.871 mmol) was added to a 250 mL Parr hydrogenation flaskcontaining a solution of benzylN-[(9R,10E,13S)-9-methyl-8-oxo-3-{[2-(trimethylsilyl)ethoxy]methyl}-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate(477 mg, 0.871 mmol) in EtOH (20 mL). The flask was purged with N₂ andpressurized to 55 psi of H₂ and allowed to stir for 4 h. The reactionwas filtered through a pad of CELITE® and concentrated to yield benzylN-[(9R,13S)-9-methyl-8-oxo-3-{[2-(trimethylsilyl)ethoxy]methyl}-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate(245 mg, 64% yield) as a tan solid. MS(ESI) m/z: 416.4 [M+H]⁺.

354G. Preparation of(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-3-{[2-(trimethylsilyl)ethoxy]methyl}-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

To a 100 mL flask containing a white suspension of6-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol(0.580 g, 1.88 mmol), prepared as described in Example 356 in ACN (25.0ml) was added HATU (0.785 g, 2.06 mmol) and DBU (0.370 ml, 2.44 mmol).The resulting clear, yellow solution was stirred at rt. After 5 min,benzylN-[(9R,13S)-9-methyl-8-oxo-3-{[2-(trimethylsilyl)ethoxy]methyl}-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate(0.780 g, 1.88 mmol) was added and the resulting suspension was stirredat rt for 3 h. The reaction was concentrated and the crude material waspurified by normal phase silica gel chromatography to give(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-3-{[2-(trimethylsilyl)ethoxy]methyl}-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(0.65 g, 0.92 mmol, 49.0% yield) isolated as a purple solid. MS(ESI)m/z: 706.7 [M+H]⁺.

354H. Preparation of(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate

To a solution of(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-3-{[2-(trimethylsilyl)ethoxy]methyl}-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(12 mg, 0.017 mmol) in DCM (0.8 mL) was added TFA (0.2 mL, 2.60 mmol)and the reaction was stirred at rt for 30 min. The reaction mixture wasthen concentrated and the residue was purified by prep HPLC purificationto give(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate (5.3 mg, 43% yield) as a pale pink solid. ¹H NMR (400MHz, CD₃OD) δ 8.72-8.57 (m, 2H), 8.37 (s, 1H), 7.99 (s, 1H), 7.91 (d,J=2.2 Hz, 1H), 7.82-7.72 (m, 2H), 7.70-7.63 (m, 2H), 6.41 (s, 1H),6.11-5.95 (m, 1H), 2.81 (td, J=6.8, 3.4 Hz, 1H), 2.44-2.17 (m, 2H),2.15-2.01 (m, 1H), 1.80-1.65 (m, 1H), 1.62-1.46 (m, 1H), 1.11 (d, J=7.0Hz, 3H), 1.01 (br. s., 1H). MS(ESI) m/z: 576.4 [M+H]⁺. Analytical HPLC(Method A): RT=6.98 min, purity=>95.0%.

354I. Preparation(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-4-(pyridin-3-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2,5,14,16-pentaen-8-one;trifluoroacetate

(9R,13S)-13-{4-[5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onemono trifluoroacetate (0.09 g, 0.16 mmol),(1R,2R)—N1,N2-dimethylcyclohexane-1,2-diamine (0.022 g, 0.16 mmol),3-iodopyridine (0.032 g, 0.16 mmol), CuI (2 mg, 10.5 μmol), Cs₂CO₃ (0.10g, 0.31 mmol), and DMF (2 mL) were added to a vial containing a Teflonseptum. The mixture was evacuated and back-filled with Ar three timesand then heated to 100° C. for 3 h. The reaction was cooled and dilutedwith 2 mL of a 9:1 ACN-H₂O solution. After filtration through a syringefilter, the product was purified by prep HPLC to yield(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-4-(pyridin-3-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2,5,14,16-pentaen-8-one;trifluoroacetate (52 mg, 42%) as a tan solid. MS(ESI) m/z: 653.6 [M+H]⁺.¹H NMR (400 MHz, CD₃OD) δ 9.31-9.24 (m, 1H), 8.80-8.73 (m, 1H),8.71-8.64 (m, 2H), 8.60 (s, 2H), 8.37 (s, 1H), 8.01-7.96 (m, 1H),7.95-7.90 (m, 1H), 7.86-7.80 (m, 1H), 7.79-7.73 (m, 2H), 7.71-7.64 (m,1H), 6.44-6.36 (m, 1H), 6.17-6.04 (m, 1H), 2.97-2.80 (m, 1H), 2.40-2.22(m, 2H), 2.15-2.00 (m, 1H), 1.82-1.69 (m, 1H), 1.69-1.52 (m, 1H),1.41-1.26 (m, 1H), 1.11 (d, J=7.0 Hz, 3H). Analytical HPLC (Method A):RT=6.69 min, purity=97.5%.

Example 355 Preparation of tert-butylN-[(1S)-1-(4-chloropyridin-2-yl)but-3-en-1-yl]carbamate

355A. Preparation of4-chloro-2-[(E)-2-[(S)-2-methylpropane-2-sulfinyl]ethenyl]pyridine

To a solution of S-(−)-t-butyl-sulfinamide (0.856 g, 7.06 mmol) in DCM(14.13 mL) was added sequentially CuSO₄ (2.481 g, 15.54 mmol) and4-chloropicolinaldehyde [1.0 g, 7.06 mmol, prepared according to amodified described by Negi (Synthesis, 991 (1996))]. The whitesuspension was stirred at rt. After 3 h, the brown suspension wasfiltered through CELITE®, eluting with DCM, to give a clear brownfiltrate. Concentration gave crude product as a brown oil weighing 1.85g. Purification by normal phase chromatography gave tert-butylN-[(1S)-1-(4-chloropyridin-2-yl)but-3-en-1-yl]carbamate (1.31 g) as aclear, yellow oil. MS(ESI) m/z: 245.0 (M+H)⁺.

355B. Preparation of(R)—N-[(1S)-1-(4-chloropyridin-2-yl)but-3-en-1-yl]-2-methylpropane-2-sulfinamide

To a cooled (0-5° C.) mixture of InCl₃ (13.56 g, 61.3 mmol) in THF (170mL) was added dropwise, over 30 min, allylmagnesium bromide (1 M inEt₂O) (62 mL, 61.3 mmol). The reaction was allowed to warm to rt. After1 h at rt, a solution of4-chloro-2-[(E)-2-[(S)-2-methylpropane-2-sulfinyl]ethenyl]pyridine (10g, 40.9 mmol) in EtOH (170 mL) was added to the reaction mixture. After2-3 h, the reaction was concentrated under vacuum at 50-55° C. The crudematerial was partitioned between EtOAc (200 ml) and water (1×50 ml) andthe layers were separated. The aqueous layer was extracted with EtOAc(2×50 ml). The organic layers were combined and washed with brine (1×100ml), dried over Na₂SO₄, filtered and concentrated to give(R)—N-[(1S)-1-(4-chloropyridin-2-yl)but-3-en-1-yl]-2-methylpropane-2-sulfinamide(13.5 g, 106%) as a yellow oil. MS(ESI) m/z: 287.2 (M+H)⁺. This materialwas used in the next step without further purification.

355C. Preparation of (1S)-1-(4-chloropyridin-2-yl)but-3-en-1-amine

(R)—N-[(1S)-1-(4-Chloropyridin-2-yl)but-3-en-1-yl]-2-methylpropane-2-sulfinamide(75 g, 261 mmol) was dissolved in MeOH (1500 mL). 6N HCl (750 ml, 4.5mol) was added. The reaction was stirred at rt for 2-3 h and then wasconcentrated. The residue was diluted with water (2 L), washed withEtOAc (500 ml). The aqueous layer was basified with saturated Na₂CO₃solution, then extracted into EtOAc (3×1 L). The combined organic layerswere washed with water (1×1 L) and brine (1×1 L), dried over Na₂SO₄,filtered and conc. under vacuum at 50-55° C. to give(1S)-1-(4-chloropyridin-2-yl)but-3-en-1-amine (43 g, 90%) which waswithout further purification. MS(ESI) m/z: 183.2 (M+H)⁺.

355D. Preparation of tert-butylN-[(1S)-1-(4-chloropyridin-2-yl)but-3-en-1-yl]carbamate

(1S)-1-(4-Chloropyridin-2-yl)but-3-en-1-amine (42 g, 230 mmol) wasdissolved in DCM (420 mL). Et₃N (32.1 mL, 230 mmol) was added followedby dropwise addition of BOC₂O (53.4 mL, 230 mmol). The reaction wasstirred at rt for 2-3 h. The reaction was diluted with excess DCM (1 L),washed with water (1×500 ml) and brine (1×500 ml). The organic layer wasdried over Na₂SO₄, filtered, and concentrated. The crude product wasthen purified using silica gel chromatography to give tert-butylN-[(1S)-1-(4-chloropyridin-2-yl)but-3-en-1-yl]carbamate (61 g, 86%) as apale yellow solid. MS(ESI) m/z: 283.2 (M+H)⁺. ¹H NMR (500 MHz, CDCl₃) δ8.44 (d, 1H), 7.26-7.16 (dd, 2H), 5.69-5.61 (m, 1H), 5.59 (bs, 1H),5.07-5.03 (m, 2H), 4.76 (bs, 1H), 2.62-2.55 (m, 2H), 1.42 (s, 9H).

Example 356 Preparation of6-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]pyrimidin-4-ol

356A. Preparation of4-chloro-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)aniline

In a 20 mL microwave vial was added 2-bromo-4-chloroaniline (3 g, 14.53mmol),4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane(5.53 g, 21.80 mmol), KOAc (3.66 g, 37.3 mmol), Pd(dppf)Cl₂—CH₂Cl₂adduct (0.32 g, 0.44 mmol) and DMSO (9 mL). The resulting suspension waspurged with N₂, capped and heated at 80° C. for 22 h. The reaction wascooled to rt. Water was added to dissolve the salts, then the reactionwas filtered. The remaining solid was suspended in DCM and the insolublesolid was filtered. The filtrate was concentrated and then purified bynormal phase chromatography to give4-chloro-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (3.15 g, 86%yield) as a white solid. MS(ESI) m/z: 172.3 (M-C₆H₁₀+H)⁺. ¹H NMR (400MHz, CDCl₃) δ 7.54 (d, J=2.6 Hz, 1H), 7.13 (dd, J=8.8, 2.6 Hz, 1H), 6.52(d, J=8.6 Hz, 1H), 4.72 (br. s., 2H), 1.34 (s, 12H).

356B. Preparation of 4-chloro-2-(6-methoxypyrimidin-4-yl)aniline

An RBF containing 4-chloro-6-methoxypyrimidine (3.13 g, 21.62 mmol),4-chloro-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (7.31 g, 21.62mmol), Na₂CO₃ (2.29 g, 21.62 mmol), DME (86 ml), EtOH (10.81 ml) andwater (10.81 ml) was equipped with a condenser. The mixture was purgedwith argon for several min, then Pd(dppf)Cl₂—CH₂Cl₂ adduct (1.77 g, 2.16mmol) was added. The reaction was heated at 90° C. for 5 h. The reactionwas cooled to rt, diluted with water and extracted with EtOAc. Theorganic layer was washed with brine, concentrated and purified by normalphase chromatography to give 4-chloro-2-(6-methoxypyrimidin-4-yl)aniline(2.86 g, 56.1% yield) as yellow solid. MS(ESI) m/z: 236.0 (M+H)⁺. 1H NMR(500 MHz, CDCl₃) δ 8.78 (d, J=1.1 Hz, 1H), 7.49 (d, J=2.5 Hz, 1H), 7.15(dd, J=8.8, 2.5 Hz, 1H), 6.99 (d, J=1.1 Hz, 1H), 6.67 (d, J=8.8 Hz, 1H),5.89 (br. s., 2H), 4.03 (s, 3H).

356C. Preparation of4-{5-chloro-2-[4-(trimethylsilyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-methoxypyrimidine

To a solution of 4-chloro-2-(6-methoxypyrimidin-4-yl)aniline (1.5 g,6.36 mmol) in ACN (90 ml) at 0° C. was added 3-methylbutyl nitrite (1.28ml, 9.55 mmol), followed by the dropwise addition ofazidotrimethylsilane (1.26 ml, 9.55 mmol). Gas evolution was observed.After 10 min, the ice bath was removed, and the reaction was allowed towarm to rt. (Caution, aryl azides are potentially explosive.) After 1 h,ethynyltrimethylsilane (2.72 ml, 19.09 mmol) and Cu₂O (0.09 g, 0.64mmol) were added and the reaction was stirred for an additional 1 h. Thereaction was partitioned in EtOAc and sat NH₄Cl, and the layers wereseparated. The organic layer was washed with brine, dried over MgSO₄,filtered and concentrated. Purification by normal phase chromatographygave4-{5-chloro-2-[4-(trimethylsilyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-methoxypyrimidine(2.13 g, 5.92 mmol, 93% yield) as a yellow solid. MS(ESI) m/z: 360.3(M+H)⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.71 (d, J=1.1 Hz, 1H), 7.82 (d, J=2.2Hz, 1H), 7.61-7.56 (m, 1H), 7.54-7.48 (m, 2H), 6.20 (d, J=1.1 Hz, 1H),3.92 (s, 3H), 0.32-0.28 (m, 9H).

356D. Preparation of4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-methoxypyrimidine

To a solution of4-{5-chloro-2-[4-(trimethylsilyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-methoxypyrimidine(1.56 g, 4.33 mmol) in ACN (28.9 ml) was added NCS (2.03 g, 15.17 mmol)and silica gel (6.51 g, 108 mmol). The reaction was stirred at 80° C.for 1 h. Then, the reaction was filtered to remove the silica gel andthe collected silica gel was washed with EtOAc. The filtrate was washedwith water (2×), brine and concentrated. Purification by normal phasechromatography gave4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-methoxypyrimidine(0.90 g, 64.5% yield) as a yellow foam. MS(ESI) m/z: 322.3 (M+H)⁺. ¹HNMR (400 MHz, CDCl₃) δ 8.70 (d, J=1.1 Hz, 1H), 7.75 (d, J=2.4 Hz, 1H),7.66-7.55 (m, 2H), 7.50 (d, J=8.6 Hz, 1H), 6.52 (d, J=0.9 Hz, 1H), 3.98(s, 3H).

356E. Preparation of6-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]pyrimidin-4-ol

To a solution of4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-methoxypyrimidine(900 mg, 2.79 mmol) in AcOH (6 ml) was added 48% HBr in water (3 ml,26.5 mmol). The mixture was stirred at 85° C. for 1 h. The reaction wasconcentrated to dryness and then partitioned between EtOAc and sataqueous NaHCO₃. The mixture was separated and the aqueous layer wasextracted with EtOAc (2×). The organic layers were combined,concentrated, and then the residue was purified by normal phasechromatography to give a white solid. The solid was suspended in Et₂O,filtered and washed with Et₂O to give6-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]pyrimidin-4-ol (610mg, 70.9% yield) as a white solid. MS(ESI) m/z: 308.3 (M+H)⁺. ¹H NMR(400 MHz, CDCl₃) δ 7.96 (s, 1H), 7.74-7.67 (m, 2H), 7.62 (dd, J=8.5, 2.3Hz, 1H), 7.47 (d, J=8.4 Hz, 1H), 6.44 (d, J=0.9 Hz, 1H).

Example 357 Preparation of (S)-benzyl(1-(4-chloropyridin-2-yl)but-3-en-1-yl)carbamate

To a solution of (1S)-1-(4-chloropyridin-2-yl)but-3-en-1-amine (15.37 g,60.1 mmol) in THF (150 mL) was added NaHCO₃ (15.16 g, 180 mmol) in H₂O(150 mL) at 0° C., followed by CBz-C₁ (12.88 mL, 90 mmol). The reactionwas then stirred at 0° C. for 2 h. The reaction mixture was diluted withEtOAc (150 mL). The organic phase was separated, washed with brine (50mL), dried over Na₂SO₄, filtered, and concentrated under reducedpressure. The crude material was purified using normal phase silica gelchromatography, eluting with a gradient of 0-20% EtOAc/petroleum ether)to obtain (S)-benzyl (1-(4-chloropyridin-2-yl)but-3-en-1-yl)carbamate(16 g, 84% yield) as a pale yellow liquid. MS(ESI) m/z: 317.5 (M+H)⁺. ¹HNMR (400 MHz, CDCl₃) δ 8.44 (d, J=5.3 Hz, 1H), 7.41-7.12 (m, 7H), 5.77(d, J=7.0 Hz, 1H), 5.72-5.57 (m, 1H), 5.16-5.00 (m, 4H), 4.86 (q, J=6.7Hz, 1H), 2.60 (t, J=6.2 Hz, 2H).

Example 358 Preparation of6-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]pyrimidin-4-ol

358A. Preparation of4-chloro-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)aniline

In a 20 mL microwave vial was added 2-bromo-4-chloroaniline (3 g, 14.53mmol),4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane(5.53 g, 21.80 mmol), KOAc (3.66 g, 37.3 mmol), Pd(dppf)Cl₂—CH₂Cl₂adduct (0.32 g, 0.44 mmol) and DMSO (9 mL). The resulting suspension waspurged with N₂, capped and heated at 80° C. for 22 h. The reaction wascooled to rt. Water was added to dissolve the salts, then the reactionwas filtered. The remaining solid was suspended in DCM and the insolublesolid was filtered. The filtrate was concentrated and then purified bynormal phase chromatography to give4-chloro-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (3.15 g, 86%yield) as a white solid. MS(ESI) m/z: 172.3 (M-C₆H₁₀+H)⁺. ¹H NMR (400MHz, CDCl₃) δ 7.54 (d, J=2.6 Hz, 1H), 7.13 (dd, J=8.8, 2.6 Hz, 1H), 6.52(d, J=8.6 Hz, 1H), 4.72 (br. s., 2H), 1.34 (s, 12H).

358B. Preparation of 4-chloro-2-(6-methoxypyrimidin-4-yl)aniline

An RBF containing 4-chloro-6-methoxypyrimidine (3.13 g, 21.62 mmol),4-chloro-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (7.31 g, 21.62mmol), Na₂CO₃ (2.29 g, 21.62 mmol), DME (86 ml), EtOH (10.81 ml) andwater (10.81 ml) was equipped with a condenser. The mixture was purgedwith argon for several minutes then Pd(dppf)Cl₂—CH₂Cl₂ adduct (1.77 g,2.16 mmol) was added. The reaction was heated at 90° C. for 5 h. Thereaction was cooled to rt, diluted with water and extracted with EtOAc.The organic layer was washed with brine, concentrated and purified bynormal phase chromatography to give4-chloro-2-(6-methoxypyrimidin-4-yl)aniline (2.86 g, 56.1% yield) asyellow solid. MS(ESI) m/z: 236.0 (M+H)⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.78(d, J=1.1 Hz, 1H), 7.49 (d, J=2.5 Hz, 1H), 7.15 (dd, J=8.8, 2.5 Hz, 1H),6.99 (d, J=1.1 Hz, 1H), 6.67 (d, J=8.8 Hz, 1H), 5.89 (br. s., 2H), 4.03(s, 3H).

358C. Preparation of4-{5-chloro-2-[4-(trimethylsilyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-methoxypyrimidine

To a solution of 4-chloro-2-(6-methoxypyrimidin-4-yl)aniline (1.5 g,6.36 mmol) in ACN (90 ml) at 0° C. was added 3-methylbutyl nitrite (1.28ml, 9.55 mmol), followed by the dropwise addition ofazidotrimethylsilane (1.26 ml, 9.55 mmol). Gas evolution was observed.After 10 min, the ice bath was removed, and the reaction was allowed towarm to rt. (Caution, aryl azides are potentially explosive.) After 1 h,ethynyltrimethylsilane (2.72 ml, 19.09 mmol) and Cu₂O (0.09 g, 0.64mmol) were added and the reaction was stirred for an additional 1 h. Thereaction was partitioned in EtOAc and saturated aqueous NH₄Cl, and thelayers were separated. The organic layer was washed with brine, driedover MgSO₄, filtered and concentrated. Purification by normal phasechromatography gave4-{5-chloro-2-[4-(trimethylsilyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-methoxypyrimidine(2.13 g, 5.92 mmol, 93% yield) as a yellow solid. MS(ESI) m/z: 360.3(M+H)⁺. 1H NMR (400 MHz, CDCl₃) δ 8.71 (d, J=1.1 Hz, 1H), 7.82 (d, J=2.2Hz, 1H), 7.61-7.56 (m, 1H), 7.54-7.48 (m, 2H), 6.20 (d, J=1.1 Hz, 1H),3.92 (s, 3H), 0.32-0.28 (m, 9H).

358D. Preparation of4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-methoxypyrimidine

To a solution of4-{5-chloro-2-[4-(trimethylsilyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-methoxypyrimidine(1.56 g, 4.33 mmol) in ACN (28.9 ml) was added NCS (2.03 g, 15.17 mmol)and silica gel (6.51 g, 108 mmol). The reaction was stirred at 80° C.for 1 h. Then, the reaction was filtered to remove the silica gel andthe collected silica gel was washed with EtOAc. The filtrate was washedwith water (2×), brine and concentrated. Purification by normal phasechromatography gave4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-methoxypyrimidine(0.90 g, 64.5% yield) as a yellow foam. MS(ESI) m/z: 322.3 (M+H)⁺. ¹HNMR (400 MHz, CDCl₃) δ 8.70 (d, J=1.1 Hz, 1H), 7.75 (d, J=2.4 Hz, 1H),7.66-7.55 (m, 2H), 7.50 (d, J=8.6 Hz, 1H), 6.52 (d, J=0.9 Hz, 1H), 3.98(s, 3H).

358E. Preparation of6-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]pyrimidin-4-ol

To a solution of4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-methoxypyrimidine(900 mg, 2.79 mmol) in AcOH (6 ml) was added 48% HBr in water (3 ml,26.5 mmol). The mixture was stirred at 85° C. for 1 h. The reaction wasconcentrated to dryness and then partitioned between EtOAc and saturatedaqueous NaHCO₃. The mixture was separated and the aqueous layer wasextracted with EtOAc (2×). The organic layers were combined,concentrated, and then the residue was purified by normal phasechromatography to give a white solid. The solid was suspended in Et₂O,filtered and washed with Et₂O to give6-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]pyrimidin-4-ol (610mg, 70.9% yield) as a white solid. MS(ESI) m/z: 308.3 (M+H)⁺. ¹H NMR(400 MHz, CDCl₃) δ 7.96 (s, 1H), 7.74-7.67 (m, 2H), 7.62 (dd, J=8.5, 2.3Hz, 1H), 7.47 (d, J=8.4 Hz, 1H), 6.44 (d, J=0.9 Hz, 1H).

Example 359 Preparation of tert-butylN-[(1S)-1-(2-bromopyridin-4-1)but-3-en-1-yl]carbamate

359A. Preparation of(R)—N-[(1E)-(2-bromopyridin-4-yl)methylidene]-2-methylpropane-2-sulfinamide

To a stirred suspension of (R)-2-methylpropane-2-sulfinamide (13.03 g,108 mmol) and Cs₂CO₃ (52.5 g, 161 mmol) in DCM (400 ml) was added2-bromopyridine-4-carbaldehyde (20 g, 108 mmol) over 10 min. Thereaction mixture was then stirred for 18.5 h at rt. The reaction mixturewas concentrated and the residue was diluted with EtOAc (50 ml) andwashed with brine (3×20 ml). The organic layer was dried over MgSO₄ andfiltered and then the filtrate was concentrated. The residue waspurified by normal phase chromatography using hexanes and EtOAc aseluents to afford (27.2 g, 87%) of(R)—N-[(1E)-(2-bromopyridin-4-yl)methylidene]-2-methylpropane-2-sulfinamideas a white solid. MS(ESI) m/z: 289-291.0 (M+H)⁺.

359B. Preparation of(R)—N-[(1S)-1-(2-bromopyridin-4-yl)but-3-en-1-yl]-2-methylpropane-2-sulfonamide

To a solution of(R)—N-[(1E)-(2-bromopyridin-4-yl)methylidene]-2-methylpropane-2-sulfinamide(0.73 g, 2.52 mmol) and indium (0.435 g, 3.79 mmol) in THF (6 ml) wasslowly added 3-bromoprop-1-ene (0.458 g, 3.79 mmol) and resultingsolution was heated at 60° C. for 18 h. The reaction mixture was cooled,filtered through CELITE® and the filtrate was concentrated. To theresidue was added EtOAc (100 ml) and 5% NaHCO₃ (aq) (1000 ml) and anemulsion formed immediately. The suspension was filtered through paper.The organic layer was washed with brine, dried over Na₂SO₄ filtered, andconcentrated. The resulting residue was purified by normal phasechromatography using hexanes and EtOAc as eluents to afford (0.62 g,74%) of(R)—N-[(1S)-1-(2-bromopyridin-4-yl)but-3-en-1-yl]-2-methylpropane-2-sulfonamideas a yellow liquid. MS(ESI) m/z: 331-333.0 (M+H)⁺.

359C. Preparation of tert-butylN-[(1S)-1-(2-bromopyridin-4-yl)but-3-en-1-yl]carbamate

To a solution of(R)—N-[(1S)-1-(2-bromopyridin-4-yl)but-3-en-1-yl]-2-methylpropane-2-sulfinamide(1.38 g, 4.17 mmol) in MeOH (10 ml) was added 4 N HCl in dioxane (5.21mL, 20.83 mmol). The reaction mixture was stirred for 1.5 h at rt, thenwas concentrated. To the resulting residue was added ACN (10 ml), TEA(5.81 ml, 41.7 mmol) and Boc₂O (1.818 g, 8.33 mmol). After 18 h, thereaction mixture was concentrated and the residue was taken up in EtOAc,washed with water, brine, dried over MgSO₄, filtered and concentrated.The resulting residue was purified by normal phase chromatography usinghexanes and EtOAc as eluents to afford (0.80 g, 58.7%) of tert-butylN-[(1S)-1-(2-bromopyridin-4-yl)but-3-en-1-yl]carbamate as a pale yellowoil. MS(ESI) m/z: 324-326.1 (M+H)⁺.

Example 360 Preparation of (R)-2-methylbut-3-enoic acid

360A. Preparation of(R)-4-benzyl-3-((R)-2-methylbut-3-enoyl)oxazolidin-2-one

To the solution of 2-methylbut-3-enoic acid (5.59 g, 55.9 mmol) and NMM(6.14 mL, 55.9 mmol) in THF (62 mL) at 0° C. was added pivaloyl chloride(6.87 mL, 55.9 mmol) dropwise. The reaction mixture was cooled down to−78° C., and stirred for ˜2 h. In a separate flask: To the solution of(R)-4-benzyloxazolidin-2-one (8.25 g, 46.6 mmol) in THF (126 mL) at −78°C. was added N-butyllithium (2.5 M in hexane) (20.49 mL, 51.2 mmol)dropwise. After 35 min, this reaction was transferred via cannula to thefirst reaction. The reaction mixture was stirred at −78° C. for 2 h,then the cold bath was removed, and the reaction was quenched withsaturated NH₄Cl. The reaction was diluted with water and extracted withEtOAc (3×). The combined organic layers were washed with brine, driedover Na₂SO₄, filtered, and concentrated to give a yellow oil (15 g).Purification by silica gel chromatography afforded(R)-4-benzyl-3-((R)-2-methylbut-3-enoyl)oxazolidin-2-one (6.59 g, 55%)as a colorless oil. MS(ESI) m/z: 282.1 (M+Na)⁺. ¹H NMR (500 MHz, CDCl₃)δ 7.36-7.19 (m, 5H), 6.03-5.93 (m, 1H), 5.23-5.10 (m, 2H), 4.69-4.63 (m,1H), 4.51-4.43 (m, 1H), 4.23-4.15 (m, 2H), 3.29 (dd, J=13.5, 3.3 Hz,1H), 2.79 (dd, J=13.5, 9.6 Hz, 1H), 1.35 (d, J=6.9 Hz, 3H) ppm. Theother diastereomer(R)-4-benzyl-3-((S)-2-methylbut-3-enoyl)oxazolidin-2-one (4.6 g, 38%)also obtained as a white solid. MS(ESI) m/z: 260.1 (M+H)⁺.

360B. Preparation of (R)-2-methylbut-3-enoic acid

To a clear colorless solution of(R)-4-benzyl-3-((R)-2-methylbut-3-enoyl) oxazolidin-2-one (6.05 g, 23.33mmol) in THF (146 mL) at 0° C. was added dropwise 30% aqueous H₂O₂ (9.53mL, 93 mmol) followed by 2 N LiOH (23.33 mL, 46.7 mmol). After 30 min,the reaction was quenched with 25 mL of saturated Na₂SO₃ and 25 mL ofsaturated NaHCO₃. The reaction was then concentrated to remove the THF.The residue was diluted with water and extracted with CHCl₃ (3×). Theaqueous layer was acidified with conc. HCl to pH-3 and then it wasextracted with EtOAc (3×). The EtOAc layers were combined, washed withbrine, dried over MgSO₄, filtered and concentrated to afford(R)-2-methylbut-3-enoic acid (2.15 g, 92%) as a colorless oil. ¹H NMR(500 MHz, CDCl₃) δ 10.84 (br. s., 1H), 5.94 (ddd, J=17.4, 10.1, 7.4 Hz,1H), 5.22-5.13 (m, 2H), 3.23-3.15 (m, 1H), 1.31 (d, J=7.2 Hz, 3H) ppm.

Example 361 Preparation of(9R,13S)-13-amino-3,9-dimethyl-3,4,7,17-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

361A. Preparation of tert-butylN-[(1S)-1-[2-(1-methyl-4-nitro-1H-pyrazol-5-yl)pyridin-4-yl]but-3-en-1-yl]carbamate

To a large microwave vial was added tert-butylN-[(1S)-1-(2-bromopyridin-4-yl)but-3-en-1-yl]carbamate (1.0 g, 3.06mmol), prepared as described in Example 354,1-methyl-4-nitro-1H-pyrazole (0.427 g, 3.36 mmol), dioxane (10 ml),di(adamantan-1-yl)(butyl)phosphine (0.164 g, 0.458 mmol), K₂CO₃ (1.267g, 9.17 mmol) and pivalic acid (0.106 ml, 0.917 mmol). The reaction wasdegassed with Ar. Afterwards, Pd(OAc)₂ (0.069 g, 0.306 mmol) was addedand the reaction was stirred at 100° C. After 4 h, heating was stoppedand the reaction was stirred at rt for 72 h. The reaction was quenchedwith water (20 ml) and extracted with EtOAc (3×50 ml). The combinedorganic layers were washed with brine (20 ml), dried (MgSO₄), andfiltered, and concentrated. The residue was purified by normal phasechromatography using heptanes and EtOAc as eluents to give tert-butylN-[(1S)-1-[2-(1-methyl-4-nitro-1H-pyrazol-5-yl)pyridin-4-yl]but-3-en-1-yl]carbamate(0.62 g, 54%) as a white foam. MS(ESI) m/z: 374.08 (M+H)⁺. ¹H NMR (500MHz, CDCl₃) δ 8.73 (d, J=5.2 Hz, 1H), 8.28-8.15 (m, 1H), 7.66-7.54 (m,1H), 7.43-7.34 (m, 1H), 5.76-5.63 (m, 1H), 5.26-5.16 (m, 2H), 4.99 (br.s., 1H), 4.83 (br. s., 1H), 3.97-3.85 (m, 3H), 2.66-2.46 (m, 2H), 1.45(br. s., 9H).

361B. Preparation of tert-butylN-[(1S)-1-[2-(4-amino-1-methyl-1H-pyrazol-5-yl)pyridin-4-yl]but-3-en-1-yl]carbamate

To a cooled (0° C.) acetone (40 ml)/water (12 ml) solution of tert-butylN-[(1S)-1-[2-(1-methyl-4-nitro-1H-pyrazol-5-yl)pyridin-4-yl]but-3-en-1-yl]carbamate(0.62 g, 1.660 mmol) was added NH₄Cl (0.444 g, 8.30 mmol) and Zn (1.086g, 16.60 mmol). The ice bath was removed and the reaction was stirred 18h. The reaction was filtered through paper and partitioned with water(20 ml) and EtOAc (75 ml). The aqueous layer was extracted with EtOAc(2×50 ml). The combined organic layers were washed with brine (25 ml)and dried (MgSO₄). The mixture was filtered, concentrated and theresidue was purified by normal phase chromatography using DCM and 0-10%MeOH as eluents to give tert-butylN-[(1S)-1-[2-(4-amino-1-methyl-1H-pyrazol-5-yl)pyridin-4-yl]but-3-en-1-yl]carbamate(0.46 g, 60%). MS(ESI) m/z: 344.5 (M+H)⁺.

361C. Preparation of tert-butylN-[(1S)-1-(2-{1-methyl-4-[(2R)-2-methylbut-3-enamido]-1H-pyrazol-5-yl}pyridin-4-yl)but-3-en-1-yl]carbamate

To tert-butylN-[(1S)-1-[2-(4-amino-1-methyl-1H-pyrazol-5-yl)pyridin-4-yl]but-3-en-1-yl]carbamate(0.6 g, 1.747 mmol) was added (R)-2-methylbut-3-enoic acid (0.189 g,1.893 mmol), prepared as described in Example 360, in EtOAc (5.8 ml),cooled to 0° C., was added pyridine (0.0.424 ml, 5.24 mmol) and a 50%EtOAc solution of T3P® (2.1 ml, 3.49 mmol). After 24 h, the reaction waspartitioned between saturated aqueous NaHCO₃ (10 ml) and EtOAc (20 ml).The aqueous layer was extracted with EtOAc (2×20 ml). The combinedorganic layers were washed with brine (10 ml) and dried (MgSO₄). Themixture was filtered and concentrated and the residue was purified bynormal phase chromatography using hexanes and EtOAc as eluents to givetert-butylN-[(1S)-1-(2-{1-methyl-4-[(2R)-2-methylbut-3-enamido]-1H-pyrazol-5-yl}pyridin-4-yl)but-3-en-1-yl]carbamate(0.35 g, 47%). MS(ESI) m/z: 426.1 (M+H)⁺. ¹H NMR (500 MHz, CDCl₃) δ10.23 (br. s., 1H), 8.70-8.56 (m, 1H), 8.35 (d, J=1.1 Hz, 1H), 7.56-7.44(m, 1H), 7.25-7.14 (m, 1H), 6.03 (ddd, J=17.2, 10.2, 8.0 Hz, 1H),5.39-5.17 (m, 3H), 5.03-4.63 (m, 2H), 4.14-4.08 (m, 3H), 3.22 (quin,J=7.2 Hz, 1H), 2.66-2.49 (m, 1H), 1.84-1.72 (m, 1H), 1.50-1.40 (m, 9H),1.42-1.37 (m, 3H), 1.06-0.93 (m, 1H).

361D. Preparation of tert-butylN-[(9R,10E,13S)-3,9-dimethyl-8-oxo-3,4,7,17-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate

To a degassed DCE (20 ml) solution of tert-butylN-[(1S)-1-(2-{1-methyl-4-[(2R)-2-methylbut-3-enamido]-1H-pyrazol-5-yl)}pyridin-4-yl)but-3-en-1-yl]carbamate(0.160 g, 0.376 mmol) was added Grubbs II (0.096 g, 0.113 mmol) and thereaction mixture was heated to 120° C. for 30 min in a microwave. Thereaction mixture was concentrated and the residue was purified by normalphase chromatography using DCM and MeOH as eluents to afford desiredproduct (29 mg, 19%) as a green film. MS(ESI) m/z: 398.3 (M+H)⁺. ¹H NMR(500 MHz, CDCl₃) δ 8.71 (d, J=4.7 Hz, 1H), 7.58 (s, 1H), 7.23 (d, J=13.8Hz, 1H), 7.03-6.94 (m, 1H), 6.61 (s, 1H), 5.82-5.71 (m, 1H), 5.19-5.09(m, 2H), 4.75 (br. s., 1H), 4.15-4.09 (m, 3H), 3.19-3.10 (m, 1H), 2.67(br. s., 1H), 2.28-2.15 (m, 2H), 1.54-1.39 (m, 9H), 1.34-1.28 (m, 3H).

361E. Preparation of(9R,13S)-13-amino-3,9-dimethyl-3,4,7,17-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

To an EtOH (3 mL) solution of tert-butylN-[(9R,10E,13S)-3,9-dimethyl-8-oxo-3,4,7,17-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate(29 mg, 0.073 mmol) was added PtO₂ (4 mg). The reaction mixture waspurged with hydrogen, then was hydrogenated at 55 psi. After 3 h, thereaction mixture was filtered through a 0.45 μM filter and concentratedto afford a dark solid (MS(ESI) m/z: 400.3 (M+H)⁺). The dark solidresidue was dissolved in 4N HCl in dioxane (1 ml) and MeOH (1 ml). After3 h, the mixture was concentrated and resultant HCl salt was dissolvedin DCM/MeOH and passed through a basic cartridge to afford(9R,13S)-13-amino-3,9-dimethyl-3,4,7,17-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-oneas a dark solid (21 mg, 96%), which was used in next step withoutfurther purification. MS(ESI) m/z: 300.2 (M+H)⁺.

Example 362 Preparation of(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,17-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate

To a solution of6-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]pyrimidin-4-ol(0.019 g, 0.060 mmol), prepared as described in Example 358, in CH₃CN(0.4 ml) was added HATU (0.030 g, 0.078 mmol) and DBU (0.014 mL, 0.090mmol). After 30 min,(9R,13S)-13-amino-3,9-dimethyl-3,4,7,17-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one,prepared as described in Example 361, was added with DMF (0.2 ml). After18 h, the reaction was diluted with DMF, filtered and concentrated. Theresidue was purified by reverse phase HPLC using PHENOMENEX® Luna 5U30×100 mm (10:90 ACN/H₂O to 90:10 ACN/H₂O, 0.1% TFA) (20% B start, 14min gradient). The desired fractions were concentrated and freeze-driedto afford(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,17-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(11.9 mg, 27%) as an off-white solid. MS(ESI) m/z: 590.3 (M+H)⁺. ¹H NMR(400 MHz, CD₃OD) δ 8.78-8.70 (m, 1H), 8.41-8.33 (m, 2H), 7.92-7.85 (m,2H), 7.80-7.73 (m, 1H), 7.71-7.65 (m, 1H), 7.51 (s, 1H), 7.21 (dd,J=5.3, 1.8 Hz, 1H), 6.50-6.42 (m, 1H), 5.77 (dd, J=12.5, 3.1 Hz, 1H),4.23-4.16 (m, 3H), 2.69-2.58 (m, 1H), 2.41 (dd, J=7.5, 4.2 Hz, 1H),2.22-2.09 (m, 1H), 2.07-1.96 (m, 1H), 1.74-1.60 (m, 1H), 1.38 (d, J=7.7Hz, 2H), 1.15 (d, J=7.0 Hz, 3H). Analytical HPLC (Method A) RT=7.38 min,purity=96%.

Example 363 Preparation of(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(²H₃)methyl-9-methyl-3,4,7,17-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate

363A. Preparation of 1-(²H₃)methyl-4-nitro-1H-pyrazole

4-Nitro-1H-pyrazole (10.3 g, 91 mmol) was dissolved in THF (200 ml) andcooled to 0° C. To this solution was added portionwise NaH (60%, 4.37 g,109 mmol) and stirred for an additional 0.5 h cold. To this cold milkysolution was then added CD₃I (6.23 ml, 100 mmol) dropwise and thereaction mixture stirred cold for 3 h, then warmed to rt and stirred atthis temperature overnight. The reaction mixture was quenched with coldwater (200 ml), extracted with EtOAc (2×200 ml) and dried with MgSO₄.The solution was filtered and concentrated yielding a yellow solid.Recrystallization of the material from hexane/ethyl acetate afforded thedesired compound as a yellow solid (11.5 g, 97%). ¹H NMR (CDCl₃) δ 8.85(s, 1H), 8.82 (s, 1H).

363B. Preparation of tert-butyl N-[(1S)-1-{2-[1-(²H₃)methyl-4-nitro-1H-pyrazol-5-yl]pyridin-4-yl}but-3-en-1-yl]carbamate

tert-Butyl N-[(1S)-1-{2-[1-(²H₃)methyl-4-nitro-1H-pyrazol-5-yl]pyridin-4-yl}but-3-en-1-yl]carbamate(0.80 g, 70%), a white foam, was prepared in the same manner astert-butyl N-[(1S)-1-[2-(1-methyl-4-nitro-1H-pyrazol-5-yl)pyridin-4-yl]but-3-en-1-yl]carbamate, as described in Example 361A, byreplacing 1-methyl-4-nitro-1H-pyrazole with1-(²H₃)methyl-4-nitro-1H-pyrazole. MS(ESI) m/z: 377.5 (M+H)⁺. ¹H NMR(500 MHz, CDCl₃) δ 8.73 (d, J=5.2 Hz, 1H), 8.28-8.15 (m, 1H), 7.59 (s,1H), 7.43-7.34 (m, 1H), 5.73-5.63 (m, 1H), 5.24-5.18 (m, 2H), 4.99 (br.s., 1H), 4.83 (br. s., 1H), 2.69-2.42 (m, 2H), 1.45 (br. s., 9H).

363C. Preparation of tert-butyl N-[(1S)-1-{2-[4-amino-1-(²H₃)methyl-1H-pyrazol-5-yl]pyridin-4-yl}but-3-en-1-yl]carbamate

tert-ButylN-[(1S)-1-{2-[4-amino-1-(²H₃)methyl-1H-pyrazol-5-yl]pyridin-4-yl}but-3-en-1-yl]carbamate(0.56 g, 76%), a tan solid, was prepared in the same manner astert-butylN-[(1S)-1-[2-(4-amino-1-methyl-1H-pyrazol-5-yl)pyridin-4-yl]but-3-en-1-yl]carbamate,as described in Example 361B, by replacing tert-butylN-[(1S)-1-[2-(1-methyl-4-nitro-1H-pyrazol-5-yl)pyridin-4-yl]but-3-en-1-yl]carbamate,prepared as described in Example 361A with tert-butylN-[(1S)-1-{2-[1-(²H₃)methyl-4-nitro-1H-pyrazol-5-yl]pyridin-4-yl}but-3-en-1-yl]carbamate.MS(ESI) m/z: 347.3 (M+H)⁺.

363D. Preparation of tert-butylN-[(1S)-1-{2-[1-(²H₃)methyl-4-[(2R)-2-methylbut-3-enamido]-1H-pyrazol-5-yl]pyridin-4-yl}but-3-en-1-yl]carbamate

tert-ButylN-[(1S)-1-{2-[1-(²H₃)methyl-4-[(2R)-2-methylbut-3-enamido]-1H-pyrazol-5-yl]pyridin-4-yl}but-3-en-1-yl]carbamate(0.49 g, 72%), a yellow solid, was prepared in the same manner astert-butylN-[(1S)-1-(2-{1-methyl-4-[(2R)-2-methylbut-3-enamido]-1H-pyrazol-5-yl}pyridin-4-yl)but-3-en-1-yl]carbamate,as described in Example 361C, by replacing tert-butylN-[(1S)-1-[2-(4-amino-1-methyl-1H-pyrazol-5-yl)pyridin-4-yl]but-3-en-1-yl]carbamate,prepared as described in Example 361B, with tert-butyl N-[(1S)-1-{2-[4-amino-1-(²H₃)methyl-1H-pyrazol-5-yl]pyridin-4-yl}but-3-en-1-yl]carbamate.MS(ESI) m/z: 429.08 (M+H)⁺. ¹H NMR (500 MHz, CDCl₃) δ 10.13 (br. s.,1H), 8.56-8.50 (m, 1H), 8.25 (s, 1H), 7.42-7.35 (m, 1H), 7.15-7.08 (m,1H), 5.92 (ddd, J=17.1, 10.1, 8.0 Hz, 1H), 5.68-5.56 (m, 1H), 5.26-5.19(m, 3H), 5.16-5.11 (m, 2H), 4.88 (br. s., 1H), 4.70 (br. s., 1H), 3.12(quin, J=7.2 Hz, 1H), 2.57-2.39 (m, 1H), 1.36 (br. s., 9H), 1.30 (d,J=6.9 Hz, 3H).

363E. Preparation of tert-butylN-[(9R,10E,13S)-3-(²H₃)methyl-9-methyl-8-oxo-3,4,7,17-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate

tert-ButylN-[(9R,10E,13S)-3-(²H₃)methyl-9-methyl-8-oxo-3,4,7,17-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate(64 mg, 33%), a green solid, was prepared in the same manner astert-butylN-[(9R,10E,13S)-3,9-dimethyl-8-oxo-3,4,7,17-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamateas described in Example 361D, by replacing tert-butylN-[(1S)-1-(2-{1-methyl-4-[(2R)-2-methylbut-3-enamido]-1H-pyrazol-5-yl}pyridin-4-yl)but-3-en-1-yl]carbamate,prepared as described in Example 361C, with tert-butylN-[(1S)-1-{2-[1-(²H₃)methyl-4-[(2R)-2-methylbut-3-enamido]-1H-pyrazol-5-yl]pyridin-4-yl}but-3-en-1-yl]carbamate.MS(ESI) m/z: 401.3 (M+H)⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.67 (br. s., 1H),7.55 (s, 1H), 7.20 (br. s., 1H), 6.97 (s, 1H), 6.75 (br. s., 1H), 5.74(br. s., 1H), 5.14 (br. s., 2H), 4.76 (br. s., 1H), 3.13 (br. s., 1H),2.66 (br. s., 1H), 2.20 (s, 1H), 1.47 (br. s., 9H), 1.28 (br. s., 3H).

363F. Preparation of(9R,13S)-13-amino-3-(²H₃)methyl-9-methyl-3,4,7,17-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

(9R,13S)-13-Amino-3-(²H₃)methyl-9-methyl-3,4,7,17-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(48 mgs), a brown solid, was prepared in the same manner as(9R,13S)-13-amino-3,9-dimethyl-3,4,7,17-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one,as described in Example 361E, replacing tert-butylN-[(9R,10E,13S)-3,9-dimethyl-8-oxo-3,4,7,17-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate,prepared as described in Example 361D, with tert-butylN-[(9R,10E,13S)-3-(²H₃)methyl-9-methyl-8-oxo-3,4,7,17-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate.MS(ESI) m/z: 303.3 (M+H)⁺.

363G. Preparation of(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(²H₃)methyl-9-methyl-3,4,7,17-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate

(9R,13S)-13-{4-[5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(²H₃)methyl-9-methyl-3,4,7,17-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate, (10.8 mg, 18%), a white solid, was prepared in thesame manner as(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,17-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one,as described in Example 362, by replacing(9R,13S)-13-amino-3,9-dimethyl-3,4,7,17-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one,prepared as described in Example 361E with(9R,13S)-13-amino-3-(²H₃)methyl-9-methyl-3,4,7,17-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one,prepared as described in Example 363F. MS(ESI) m/z: 593.3 (M+H)⁺. ¹H NMR(400 MHz, CD₃OD) δ 8.78-8.69 (m, 1H), 8.42-8.33 (m, 2H), 7.92-7.86 (m,2H), 7.80-7.74 (m, 1H), 7.69-7.64 (m, 1H), 7.52 (s, 1H), 7.21 (dd,J=5.3, 1.5 Hz, 1H), 6.51-6.43 (m, 1H), 5.77 (dd, J=12.5, 3.3 Hz, 1H),2.62 (ddd, J=9.5, 6.7, 3.4 Hz, 1H), 2.48-2.38 (m, 1H), 2.22-2.11 (m,1H), 2.06-1.97 (m, 1H), 1.69-1.59 (m, 1H), 1.42-1.33 (m, 2H), 1.15 (d,J=6.8 Hz, 3H). Analytical HPLC (Method A) RT=7.26 min, purity=96%.

Example 364 Preparation of6-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}pyrimidin-4-ol

364A. Preparation of4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-methoxypyrimidine

To a solution of 4-chloro-2-(6-methoxypyrimidin-4-yl)aniline (1.0 g,4.24 mmol), prepared as described in Example 358B, in ACN (60.6 ml) at0° C. was added 3-methylbutyl nitrite (0.86 ml, 6.36 mmol) followed bythe dropwise addition of azidotrimethylsilane (0.84 ml, 6.36 mmol). Gasevolution was observed. After 10 min, the ice bath was removed, and thereaction was allowed to warm to rt. (Caution, aryl azides arepotentially explosive.) After 2 h, Cu₂O (61 mg, 0.42 mmol) was addedfollowed by a slow bubbling of 3,3,3-trifluoroprop-1-yne gas over aperiod of 5 min. After an additional 10 min, the reaction waspartitioned between DCM and saturated aqueous NH₄Cl and then the layerswere separated. The organic layer was washed with brine, dried overMgSO₄, filtered and concentrated. Purification by normal phasechromatography gave4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-methoxypyrimidine(1.46 g, 97% yield) as a yellow solid. MS(ESI) m/z: 356.1 (M+H)⁺. ¹H NMR(400 MHz, CDCl₃) δ 8.62 (d, J=1.1 Hz, 1H), 8.00 (d, J=0.7 Hz, 1H), 7.75(d, J=2.4 Hz, 1H), 7.66-7.60 (m, 1H), 7.52 (d, J=8.6 Hz, 1H), 6.60 (d,J=1.1 Hz, 1H), 3.98 (s, 3H). ¹⁹F NMR (376 MHz, CDCl₃) δ −61.10 (s).

364B. Preparation of6-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}pyrimidin-4-ol

To a solution of4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-methoxypyrimidine(1.46 g, 4.10 mmol) in AcOH (10 ml) was added 48% HBr in water (5 ml,44.2 mmol). The mixture was stirred at 85° C. for 1 h. The reaction wasconcentrated to dryness and then partitioned between EtOAc and saturatedaqueous NaHCO₃ solution. The layers were separated and the aqueous layerwas extracted with EtOAc (2×). The organic layers were combined andwashed with saturated aqueous NaHCO₃, brine, dried over MgSO₄, filteredand the solvent was reduced under vacuum until some solid started toform. The resulting suspension was triturated with Et₂O. The solid wasfiltered and washed with Et₂O to give6-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}pyrimidin-4-ol(1 g, 71.3% yield) as a pale yellow solid. MS(ESI) m/z: 342.0 (M+H)⁺. ¹HNMR (400 MHz, CD₃OD) δ 8.83 (d, J=0.7 Hz, 1H), 7.99 (d, J=0.9 Hz, 1H),7.87 (d, J=2.2 Hz, 1H), 7.79-7.72 (m, 1H), 7.70-7.62 (m, 1H), 6.45 (d,J=0.9 Hz, 1H). ¹⁹F NMR (376 MHz, CD₃OD) δ −62.61 (s).

Example 365 Preparation of(9R,13S)-13-amino-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

365A. Preparation of 1-methyl-4-nitro-1H-pyrazole

To a solution of 4-nitro-1H-pyrazole (2.5 g, 22.11 mmol) in THF (50 mL)was added NaH (0.973 g, 24.32 mmol) and the mixture was stirred at rtfor 5 min. To this suspension was then added CH₃I (1.382 mL, 22.11 mmol)and stirred at rt overnight. The reaction mixture was then diluted withEtOAc (2×25 mL) and washed with brine (25 mL). The organic layer wasconcentrated, followed by purification using normal phase chromatographyto yield 1-methyl-4-nitro-1H-pyrazole as white solid (1.9 g, 80% yield).¹H NMR (400 MHz, CDCl₃) δ ppm 8.12 (s, 1H), 8.06 (s, 1H), 3.97 (s, 3H).

365B. Preparation of (S)-tert-butyl(1-(4-(1-methyl-4-nitro-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate

To a N₂ flushed pressure vial was added (S)-tert-butyl(1-(4-chloropyridin-2-yl)but-3-en-1-yl)carbamate (3.0 g, 10.61 mmol),1-methyl-4-nitro-1H-pyrazole (1.348 g, 10.61 mmol),di(adamant-1-yl)(butyl)phosphine (1.141 g, 3.18 mmol), PvOH (0.369 ml,3.18 mmol) and K₂CO₃ (4.40 g, 31.8 mmol). To the above mixture was thenadded DMF (21 mL) and the vial was purged with N₂ for 5 min. To thismixture was then added Pd(OAc)₂ (0.476 g, 2.122 mmol). The reactionmixture was again briefly purged with N₂. The vial was sealed and heatedin oil bath at 120° C. for 4 h. The reaction mixture was cooled to rtand partitioned between 10% aqueous LiCl (15 mL) and EtOAc (30 mL). Theaqueous layer was extracted with EtOAc (2×20 mL) and the combinedorganic layers were washed with brine (15 mL), dried over MgSO₄,filtered and concentrated. The crude product was then purified usingnormal phase chromatography to yield (S)-tert-butyl(1-(4-(1-methyl-4-nitro-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate(1.2 g, 29% yield) as a brown oil. MS(ESI) m/z: 374.4 (M+H)⁺.

365C. Preparation of (S)-tert-butyl(1-(4-(4-amino-1-methyl-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate

A solution of (S)-tert-butyl(1-(4-(1-methyl-4-nitro-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate(1.2 g, 3.21 mmol) in MeOH (10 mL) and AcOH (1 mL) was heated in oilbath to 40° C. To the above clear solution was then slowly added Zn(0.420 g, 6.43 mmol, in 3 portions (50:25:25%) and allowed to stir atthe same temperature for 5 min. The reaction mixture was monitored byLCMS and once reaction is complete, to the cooled reaction mixture wasthen added 1 g of K₂CO₃ (1 g for 1 mL AcOH) and 1 mL water. The reactionmixture was then stirred for 5 min. The reaction mixture was thenfiltered over a pad of CELITE® and concentrated in vacuo to yield thecrude product. The crude product was then partitioned between EtOAc (30mL) and saturated aqueous NaHCO₃ (15 mL) solution. The organic layerswere separated, dried over MgSO₄, filtered and concentrated. The crudeproduct was then purified using normal phase chromatography to yield(S)-tert-butyl(1-(4-(4-amino-1-methyl-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate(0.88 g, 76% yield) as pale brown oil. MS(ESI) m/z: 344.4 (M+H)⁺.

365D. Preparation of tert-butyl((S)-1-(4-(1-methyl-4-((R)-2-methylbut-3-enamido)-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate

To a N₂ flushed, 3-necked, 250 mL RBF was added a solution of(S)-tert-butyl(1-(4-(4-amino-1-methyl-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate(620 mg, 1.805 mmol) and EtOAc (15 mL). The solution was cooled to −10°C. and (R)-2-methylbut-3-enoic acid, as prepared in Example 354, (271mg, 2.71 mmol), pyridine (0.437 mL, 5.42 mmol) and T3P® (2.149 mL, 3.61mmol) were added. The cooling bath was removed and the solution wasallowed to warm to rt and then stir over a period of 20 h. Water (15 mL)and EtOAc (15 mL) were added and the mixture was stirred for 30 min. Theorganic phase was separated and the aqueous layer was extracted withEtOAc (15 mL). The combined organic extracts were washed with brine (15mL), dried over Na₂SO₄, filtered and concentrated in vacuo. Purificationby normal phase chromatography eluting with a gradient of hexanes/EtOAcgave tert-butyl((S)-1-(4-(1-methyl-4-((R)-2-methylbut-3-enamido)-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate(0.26 g, 34% yield). MS(ESI) m/z: 426.5 [M+H]⁺.

365E. Preparation of tert-butylN-[(9R,10E,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate

To a N₂ flushed, 250 mL, 3-necked RBF was added a solution of tert-butyl((S)-1-(4-(1-methyl-4-((R)-2-methylbut-3-enamido)-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate(266 mg, 0.625 mmol) in DCE (18 mL). The solution was sparged with argonfor 15 min. Grubbs II (213 mg, 0.250 mmol) was added in one portion. Thereaction mixture was heated to 120° C. in microwave for 30 min. Aftercooling to rt, the solvent was removed and the residue was purified bynormal phase chromatography eluting with a gradient of DCM/MeOH to yieldtert-butylN-[(9R,10E,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate(60 mg, 23% yield) as a tan solid. MS(ESI) m/z: 398.4 [M+H]⁺.

365F. Preparation of tert-butylN-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate

Pd/C (0.016 g, 0.015 mmol) was added to a 100 mL Parr hydrogenationflask containing a solution of tert-butylN-[(9R,10E,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate(60 mg, 0.151 mmol) in EtOH (6 mL). The flask was purged with N₂ andpressurized to 55 psi of H₂ and allowed to stir for 5 h. The reactionwas filtered through a pad of CELITE® and concentrated to yieldtert-butylN-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate(48 mg, 76% yield) as a tan solid. MS(ESI) m/z: 400.5 [M+H]⁺.

365G. Preparation of(9R,13S)-13-amino-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

To a solution of tert-butylN-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate(48 mg, 0.120 mmol) in DCM (2.5 mL) was added TFA (0.6 mL, 7.79 mmol)and the reaction was stirred at rt for 1.5 h. The reaction mixture wasthen concentrated to give(9R,13S)-13-amino-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onebis trifluoroacetate (63 mg, 94% yield) as a brown solid which was thendissolved in MeOH (1 mL) to give a clear, brown solution. The solutionwas added to a pre-rinsed AGILENT® StratoSpheres SPE PL-HCO₃ MP Resincartridge. Gravity filtration, eluting with MeOH, gave a clear, slightlyyellow filtrate. Concentration provided(9R,13S)-13-amino-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(25 mg, 93%) as a pale yellow solid. MS(ESI) m/z: 300.4 [M+H]⁺.

Example 366 Preparation of(9R,13S)-13-amino-3-(²H₃)methyl-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

366A. Preparation of 1-(²H₃)methyl-4-nitro-1H-pyrazole

DIAD (5.59 mL, 28.7 mmol) was added to a solution of 4-nitro-1H-pyrazole(2.5 g, 22.11 mmol), CD₃OD (0.898 mL, 22.11 mmol), and Ph₃P (resinbound) (8.84 g, 26.5 mmol) in THF (40 ml) and stirred overnight. Thereaction was quenched with water, extracted with EtOAc, washed withbrine, dried over Na₂SO₄, filtered, and concentrated. The crude productwas purified by normal phase chromatography eluting with a gradient ofDCM/MeOH to afford the desired product (1.92 g, 14.76 mmol, 66.7% yield)as a white solid. MS(ESI) m/z: 131.0 (M+H)⁺. ¹H NMR (400 MHz, CDCl₃) δ8.13 (d, J=0.4 Hz, 1H), 8.05 (s, 1H).

366B. Preparation of tert-butylN-[(1S)-1-{4-[1-(²H₃)methyl-4-nitro-1H-pyrazol-5-yl]pyridin-2-yl}but-3-en-1-yl]carbamate

To a large microwave vial were added (S)-tert-butyl(1-(4-chloropyridin-2-yl)but-3-en-1-yl)carbamate (2.61 g, 9.22 mmol),1-(²H₃)methyl-4-nitro-1H-pyrazole (1.0 g, 7.69 mmol),di(adamantanyl)(butyl)phosphine (0.413 g, 1.15 mmol), K₂CO₃ (3.19 g,23.06 mmol) and pivalic acid (0.268 ml, 2.306 mmol) and DMF (15.37 ml).The reaction was purged with argon for 10 min, Pd(OAc)₂ (0.173 g, 0.769mmol) was added, vial sealed, and stirred at 115° C. overnight. Thereaction was then partitioned between EtOAc and H₂O. The aqueous layerwas extracted with additional EtOAc (2×). The combined organic layer waswashed with brine, dried over MgSO₄, filtered and concentrated. Theresidue was purified by normal phase chromatography eluting with agradient of hexanes/EtOAc to give the desired product (1.49 g, 3.96mmol, 51.5% yield) as a lavender foam. MS(ESI) m/z: 377.0 (M+H)⁺. ¹H NMR(400 MHz, CDCl₃) δ 8.77 (d, J=4.8 Hz, 1H), 8.21 (s, 1H), 7.26 (s, 1H),7.23 (dd, J=5.1, 1.5 Hz, 1H), 5.78-5.65 (m, 1H), 5.55 (d, J=6.8 Hz, 1H),5.14-5.03 (m, 2H), 4.89 (d, J=6.8 Hz, 1H), 2.66 (t, J=6.6 Hz, 2H), 1.44(s, 9H).

366C. Preparation of tert-butylN-[(1S)-1-{4-[4-amino-1-(²H₃)methyl-1H-pyrazol-5-yl]pyridin-2-yl}but-3-en-1-yl]carbamate

tert-ButylN-[(1S)-1-{4-[1-(²H₃)methyl-4-nitro-1H-pyrazol-5-yl]pyridin-2-yl}but-3-en-1-yl]carbamate(1.45 g, 3.85 mmol) was dissolved in acetone (15 ml)/water (3 ml),cooled to 0° C., and added NH₄Cl (1.030 g, 19.26 mmol) and zinc (2.52 g,38.5 mmol) followed by removal of ice bath. After 1 h, the reaction wasfiltered and filtrate partitioned with water (30 ml) and EtOAc (50 ml).The aqueous layer was extracted with EtOAc (2×50 ml). The combinedorganic layers were washed with brine (20 ml), dried (MgSO₄), filtered,and concentrated. The residue was purified by normal phase eluting witha gradient of DCM/MeOH chromatography to afford the desired product(0.62 g, 46.5%). MS(ESI) m/z: 347.2 (M+H)⁺. ¹H NMR (400 MHz, CDCl₃) δ8.67 (dd, J=5.1, 0.7 Hz, 1H), 7.26-7.23 (m, 2H), 7.21 (dd, J=5.1, 1.5Hz, 1H), 5.79-5.66 (m, 1H), 5.58 (d, J=7.3 Hz, 1H), 5.11-5.05 (m, 2H),4.86 (q, J=6.6 Hz, 1H), 2.64 (t, J=6.7 Hz, 2H), 1.44 (s, 9H).

366D. Preparation of tert-butylN-[(1S)-1-{4-[1-(²H₃)methyl-4-[(2R)-2-methylbut-3-enamido]-1H-pyrazol-5-yl]pyridin-2-yl)}but-3-en-1-yl]carbamate

(R)-2-Methylbut-3-enoic acid (233 mg, 2.327 mmol), tert-butylN-[(1S)-1-{4-[4-amino-1-(²H₃)methyl-1H-pyrazol-5-yl]pyridin-2-yl}but-3-en-1-yl]carbamate(620 mg, 1.79 mmol), pyridine (0.433 ml, 5.37 mmol) in EtOAc (17.900 ml)was cooled to −10° C. under Ar followed by dropwise addition of T3P®(50% wt in EtOAc) (2.131 ml, 3.58 mmol) was added dropwise and thengradually warmed up to rt. After 3.5 h, the reaction mixture was dilutedwith EtOAc, washed with 1.5 M K₂HPO₄ followed by brine, dried overNa₂SO₄, filtered, and concentrated. The crude product was then purifiedby normal phase chromatography eluting with a gradient of hexanes/EtOActo the desired product (529 mg, 1.234 mmol, 69.0% yield) as a yellowfoam. MS(ESI) m/z: 429.2 (M+H)⁺.

366E. Preparation of tert-butylN-[(9R,10E,13S)-3-(²H₃)methyl-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate

Five large microwave vials were charged in equal amounts with thefollowing: tert-butylN-[(1S)-1-{4-[1-(²H₃)methyl-4-[(2R)-2-methylbut-3-enamido]-1H-pyrazol-5-yl]pyridin-2-yl}but-3-en-1-yl]carbamate(0.51 g, 1.190 mmol) in degassed DCE (90 ml) was irradiated 120° C. for30 min in the presence of Grubbs II (0.404 g, 0.476 mmol). The reactionswere combined, concentrated, and the residue purified by normal phasecolumn chromatography eluting with a gradient of hexanes/EtOAc to givethe desired product (0.124 g, 26.0%) as a brown solid. MS(ESI) m/z:401.2 (M+H)⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.66 (d, J=5.1 Hz, 1H), 7.52 (s,1H), 7.19 (d, J=4.8 Hz, 1H), 6.80 (s, 1H), 6.37 (d, J=7.5 Hz, 1H), 5.68(t, J=11.2 Hz, 1H), 4.82-4.63 (m, 2H), 3.12-2.93 (m, 2H), 1.93 (q,J=11.1 Hz, 1H), 1.48 (s, 9H), 1.15 (d, J=5.9 Hz, 3H).

366F. Preparation of tert-butylN-[(9R,13S)-3-(²H₃)methyl-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate

PtO₂ (6.80 mg, 0.030 mmol) was added to a stirring solution oftert-butylN-[(9R,10E,13S)-3-(²H₃)methyl-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate(0.120 g, 0.300 mmol) in EtOH (10 ml). The suspension was subjected to ahydrogen atmosphere (55 psi) for 1 h. The catalyst was filtered offthrough a plug of CELITE® and the filtrate concentrated. The product(0.104 g, 86%) was carried forward to the next reaction as is withoutfurther purification. MS(ESI) m/z: 403.2 (M+H)⁺.

366G. Preparation of(9R,13S)-13-amino-3-(²H₃)methyl-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

A solution of 4.0 M HCl in dioxane (1.621 ml) was added to a stirringsolution of tert-butylN-[(9R,13S)-3-(²H₃)methyl-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate(0.100 g, 0.248 mmol) in MeOH (3 ml) and stirred overnight. The reactionmixture was concentrated to dryness and placed under high vacuum. Thehydrogen chloride salt was free based by dissolution in MeOH, passedthrough a resin bound NaHCO₃ cartridge (StratoSpheres SPE; 500 mg, 0.90mmol loading) and filtrate concentrated. The material was carriedforward as is to next reaction. MS(ESI) m/z: 303.4 (M+H)⁺.

Example 367 Preparation of(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate

To a scintillation vial containing6-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}pyrimidin-4-ol(22.8 mg, 0.067 mmol), prepared as described in Example 364, HATU (33.0mg, 0.087 mmol) in anhydrous ACN (0.5 mL) was added DBU (15 mL, 0.100mmol). After 30 min, a solution of(9R,13S)-13-amino-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(20 mg, 0.067 mmol), prepared as described in Example 365, in 0.5 mlCH₃CN and DMF (0.1 ml) was added. The resulting solution was stirred atrt for 2 h then purified by reverse phase chromatography to give, afterconcentration and lyophilization,(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate (26.98 mg, 53.1% yield) as a white solid. MS(ESI) m/z:624.3 (M+H)⁺. ¹H NMR (400 MHz, CD₃OD) d 8.81 (d, J=0.7 Hz, 1H), 8.75 (s,1H), 8.70 (d, J=5.3 Hz, 1H), 7.89 (d, J=2.4 Hz, 1H), 7.77-7.72 (m, 1H),7.72-7.66 (m, 2H), 7.53 (dd, J=5.1, 1.5 Hz, 1H), 7.49 (s, 1H), 6.43 (s,1H), 6.02-5.93 (m, 1H), 4.04 (s, 3H), 2.70 (td, J=6.7, 3.3 Hz, 1H), 2.27(tt, J=12.7, 4.4 Hz, 1H), 2.12-1.94 (m, 2H), 1.66-1.52 (m, 1H), 1.45(ddd, J=15.0, 9.8, 5.0 Hz, 1H), 1.00 (d, J=7.0 Hz, 3H), 0.69 (br. s.,1H). ¹⁹F NMR (376 MHz, CD₃OD) d −62.54 (s), −77.44 (s). Analytical HPLC(Method A): RT=11.02 min, purity=96.7%.

Example 368 Preparation of(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(²H₃)methyl-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate

(9R,13S)-13-(4-{5-Chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(²H₃)methyl-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate (11 mg, 30% yield) was prepared in a similar manner asthe procedure described in Example 367, by replacing(9R,13S)-13-amino-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onewith(9R,13S)-13-amino-3-(²H₃)methyl-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(15 mg, 0.050 mmol), prepared as described in Example 366. MS(ESI) m/z:627.3 (M+H). ¹H NMR (400 MHz, CD₃OD) δ 8.81 (s, 1H), 8.77-8.66 (m, 2H),7.89 (d, J=2.2 Hz, 1H), 7.79-7.64 (m, 3H), 7.59-7.51 (m, 1H), 7.49 (s,1H), 6.44 (s, 1H), 5.97 (dd, J=12.4, 3.9 Hz, 1H), 2.76-2.62 (m, J=6.5,3.4, 3.4 Hz, 1H), 2.34-2.21 (m, 1H), 2.12-1.94 (m, 2H), 1.68-1.53 (m,1H), 1.51-1.39 (m, 1H), 1.00 (d, J=6.8 Hz, 3H), 0.78-0.63 (m, 1H).Analytical HPLC (Method A): RT=8.64 min, purity=99.4%.

Example 369 Preparation of(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate

(9R,13S)-13-(4-{5-Chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one,trifluoroacetate (20 mg, 50% yield) was prepared in a similar manner asthe procedure described in Example 367, by replacing(9R,13S)-13-amino-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one,with(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(17 mg, 0.051 mmol). MS(ESI) m/z: 660.3 (M+H). ¹H NMR (400 MHz, CD₃OD) δ8.81 (d, J=3.7 Hz, 2H), 8.71 (d, J=5.1 Hz, 1H), 7.89 (d, J=2.2 Hz, 1H),7.81-7.62 (m, 5H), 7.56-7.46 (m, 1H), 6.44 (s, 1H), 6.00 (dd, J=12.7,4.5 Hz, 1H), 2.70 (td, J=6.5, 3.0 Hz, 1H), 2.32-2.20 (m, 1H), 2.10-1.91(m, 2H), 1.65-1.51 (m, 1H), 1.51-1.39 (m, 1H), 0.99 (d, J=6.8 Hz, 3H),0.70-0.51 (m, 1H). Analytical HPLC (Method A): RT=9.74 min,purity=97.8%.

Example 370 Preparation of(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,17-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate

(9R,13S)-13-(4-{5-Chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,17-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one,TFA salt (9 mg, 20%), an off-white solid, was prepared in the samemanner as Example 362, replacing6-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]pyrimidin-4-ol,prepared as described in Example 358, with6-{5-chloro-2-[4-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}pyrimidin-4-ol,prepared as described in Example 364B. MS(ESI) m/z: 624.3 (M+H)⁺. ¹H NMR(400 MHz, CD₃OD) δ 8.84 (d, J=0.7 Hz, 1H), 8.71 (d, J=5.1 Hz, 1H), 8.29(s, 1H), 7.91 (d, J=2.4 Hz, 1H), 7.86 (s, 1H), 7.80-7.75 (m, 1H), 7.72(s, 1H), 7.51 (s, 1H), 7.17 (dd, J=5.3, 1.8 Hz, 1H), 6.52 (d, J=0.7 Hz,1H), 5.77 (dd, J=12.4, 3.2 Hz, 1H), 4.18 (s, 3H), 2.64-2.56 (m, 1H),2.38 (br. s., 1H), 2.11 (dd, J=13.1, 3.6 Hz, 1H), 2.02-1.95 (m, 1H),1.64 (d, J=6.8 Hz, 1H), 1.39 (dd, J=16.9, 8.1 Hz, 2H), 1.14 (d, J=6.8Hz, 3H). Analytical HPLC (Method A) RT=8.05 min, purity=95%.

Example 371 Preparation of(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(²H₃)methyl-9-methyl-3,4,7,17-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate

(9R,13S)-13-(4-{5-Chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(²H₃)methyl-9-methyl-3,4,7,17-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate (11.7 mg, 23%), an off-white solid, was prepared in thesame manner as Example 362, replacing6-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]pyrimidin-4-ol,prepared as described in Example 358, with6-{5-chloro-2-[4-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}pyrimidin-4-ol,prepared as described in Example 364B. Also,(9R,13S)-13-amino-3,9-dimethyl-3,4,7,17-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one,prepared as described in Example 361 was replaced with(9R,13S)-13-amino-3-(²H₃)methyl-9-methyl-3,4,7,17-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one,prepared as described in Example 358F. MS(ESI) m/z: 627.3 (M+H)⁺. ¹H NMR(400 MHz, CD₃OD) δ 8.86-8.82 (m, 1H), 8.75-8.69 (m, 1H), 8.28 (s, 1H),7.94-7.87 (m, 1H), 7.86 (s, 1H), 7.80-7.76 (m, 1H), 7.74-7.69 (m, 1H),7.51 (s, 1H), 7.20-7.09 (m, 1H), 6.56-6.51 (m, 1H), 5.77 (dd, J=12.5,3.3 Hz, 1H), 2.67-2.58 (m, 1H), 2.47-2.37 (m, 2H), 2.19-2.06 (m, 1H),2.03-1.96 (m, 1H), 1.73-1.60 (m, 1H), 1.48-1.31 (m, 2H), 1.14 (d, J=6.8Hz, 3H). Analytical HPLC (Method A) RT=8.02 min, purity=96%.

Example 372 Preparation of1-(4-chloro-2-(1-((5R,9S)-21,5-dimethyl-4-oxo-21H-3-aza-1(2,4)-pyridina-2(5,4)-pyrazolacyclononaphane-9-yl)-6-oxo-1,6-dihydropyrimidin-4-yl)phenyl)-1H-1,2,3-triazole-4-carboxylicacid trifluoroacetate

372A. Preparation ofN-(4-chloro-2-(6-methoxypyrimidin-4-yl)phenyl)-2,2,2-trifluoroacetamide

TEA (0.371 ml, 2.66 mmol) was added to a solution of4-chloro-2-(6-methoxypyrimidin-4-yl)aniline (0.523 g, 2.219 mmol),prepared as described in Example 358B, and trifluoroacetic anhydride(0.376 ml, 2.66 mmol) in DCM (17.47 ml). After 1 h, the reaction mixturewas concentrated and purified by normal phase chromatography to giveN-(4-chloro-2-(6-methoxypyrimidin-4-yl)phenyl)-2,2,2-trifluoroacetamide(0.684 g, 93% yield) as a white solid. MS(ESI) m/z: 332.1 (M+H)⁺. ¹H NMR(400 MHz, CDCl₃-d) δ 13.95 (br. s., 1H), 8.83 (d, J=1.1 Hz, 1H), 8.59(d, J=9.0 Hz, 1H), 7.76 (d, J=2.4 Hz, 1H), 7.49 (dd, J=9.0, 2.4 Hz, 1H),7.16 (d, J=0.9 Hz, 1H), 4.09 (s, 3H).

372B. Preparation ofN-(4-chloro-2-(6-hydroxypyrimidin-4-yl)phenyl)-2,2,2-trifluoroacetamide

48% HBr in H₂O (1.693 ml, 14.97 mmol) was added to a stirring solutionofN-(4-chloro-2-(6-methoxypyrimidin-4-yl)phenyl)-2,2,2-trifluoroacetamide(0.68 g, 2.05 mmol) in THF (13.67 ml) at 60° C. After 3 h, the reactionmixture was concentrated, quenched with saturated NaHCO₃ (40 ml), andextracted with EtOAc (3×30 ml). The combined organic layers were washedwith brine (15 mL) and dried (MgSO₄). The residue was purified by normalphase chromatography to give the desired product (0.195 g, 30%). MS(ESI)m/z: 318.1 (M+H)⁺. ¹H NMR: (400 MHz, CDCl₃-d) δ 8.50 (d, J=9.0 Hz, 1H),8.27 (s, 1H), 7.66 (d, J=2.4 Hz, 1H), 7.57-7.49 (m, 1H), 6.89 (s, 1H).

372C. Preparation of(5R,9S)-9-(4-(2-amino-5-chlorophenyl)-6-oxopyrimidin-1(6H)-yl)-21,5-dimethyl-21H-3-aza-1(2,4)-pyridina-2(5,4)-pyrazolacyclononaphan-4-one

To a 1-dram vial containing a white suspension ofN-(4-chloro-2-(6-hydroxypyrimidin-4-yl)phenyl)-2,2,2-trifluoroacetamide(0.035 g, 0.110 mmol) and HATU (0.054 g, 0.143 mmol) in ACN (1.10 ml)was added DBU (0.025 ml, 0.165 mmol). After 10 min, a purple solution ofExample 361 (0.033 g, 0.110 mmol) in DMF (1.102 ml) was added. Afterstirring overnight, the reaction was diluted with water, extracted withEtOAc (3×), organics washed with brine, dried over Na₂SO₄, filtered andconcentrated. The crude product was purified by normal phasechromatography to give the desired intermediate as a yellow film (30%undesired isomer also observed in ¹H NMR). The material was carriedforward to subsequent reactions. The trifluoroacetamide group wasremoved by dissolving the compound in MeOH (2 ml), treatment with HCl (1ml), and heating to 75° C. After 2 h, the organics were removed and theaqueous layer freeze dried. The HCl salt was neutralized by dissolvingthe residue in MeOH and passing through two successive NaHCO₃ cartridges(500 mg) and filtrate concentrated to give the desired product (0.040 g,0.079 mmol, 72.0% yield) as a yellow film. MS(ESI) m/z: 504.3 (M+H)⁺.

372D. Preparation of1-(4-chloro-2-(1-((5R,9S)-21,5-dimethyl-4-oxo-21H-3-aza-1(2,4)-pyridina-2(5,4)-pyrazolacyclononaphane-9-yl)-6-oxo-1,6-dihydropyrimidin-4-yl)phenyl)-1H-1,2,3-triazole-4-carboxylicacid trifluoroacetate

To a yellow solution of 20 C (0.040 g, 0.079 mmol) in ACN (1.134 ml) at0° C. was added isoamyl nitrite (0.032 ml, 0.238 mmol) in ACN (0.25 ml),followed by azidotrimethylsilane (0.031 ml, 0.238 mmol) ACN (0.25 ml),dropwise. After 10 min, the cold bath was removed, and the reactionallowed to warm to rt. After 1 h, tert-butyl propiolate (0.050 g, 0.397mmol) ACN (0.25 ml), and Cu₂₀ (1.136 mg, 7.94 μmol) were added at rt.After 6 h, the reaction was diluted with DCM and washed with sat. NH₄Cl,brine, dried over MgSO₄, filtered and concentrated to give a yellow oil.The crude material was purified by normal phase chromatography to givethe desired intermediate as a yellow film. The t-butyl ester washydrolyzed by treatment with 50%/TFA/DCM. After 1 h, the reactionmixture was concentrated, purified by reverse phase chromatography, andfreeze dried to give the desired product (15 mg, 25%). This material wassubjected to chiral purification to remove any remaining residualundesired isomer. The title compound was the early eluting isomer afterchiral HPLC separation using CHIRALPAK® IC, 21×250 mm ID, 5μ, using 40%MeOH:ACN:FA/60% CO₂ at 45.0 mL/min, 100 bar, and 40° C. MS(ESI) m/z:600.3 (M+H)⁺. ¹H NMR: (400 MHz, ACN-d3) d 8.66 (d, J=5.1 Hz, 1H), 8.41(s, 1H), 8.07 (s, 1H), 7.83-7.77 (m, 2H), 7.73-7.66 (m, 2H), 7.65-7.61(m, 1H), 7.37 (s, 1H), 6.99 (d, J=4.2 Hz, 1H), 6.39 (s, 1H), 5.66-5.61(m, 1H), 4.12 (s, 3H), 2.52 (br. s., 1H), 2.25-2.19 (m, 1H), 2.07-2.01(m, 1H), 1.54 (dd, J=13.4, 5.5 Hz, 1H), 1.31 (d, J=7.9 Hz, 1H),1.19-1.14 (m, 1H), 1.05 (d, J=6.8 Hz, 3H). Analytical HPLC (Method A)RT=5.31 min, purity>95%.

Example 373 Preparation of1-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)-1H-1,2,3-triazole-4-carboxylicacid trifluoroacetate

373A. Preparation of ethyl1-[4-chloro-2-(6-methoxypyrimidin-4-yl)phenyl]-1H-1,2,3-triazole-4-carboxylate

To a cooled (0° C.) clear, yellow solution of4-chloro-2-(6-methoxypyrimidin-4-yl)aniline (0.400 g, 1.70 mmol),prepared as described in Example 356B, in CH₃CN (24.2 mL) was addedisoamyl nitrite (0.34 mL, 2.55 mmol), followed by the dropwise additionof azidotrimethylsilane (0.34 mL, 2.55 mmol). Gas evolution wasobserved. After 10 min, the cold bath was removed and the reaction wasallowed to warm to rt and stir at rt for 1 h. A yellow suspensionformed. Next, ethyl propiolate (0.500 g, 5.09 mmol) and Cu₂O (0.024 g,0.17 mmol) were added. After 1 h, the cloudy greenish reaction wasdiluted with DCM and washed with saturated aqueous NH₄Cl, brine, driedover MgSO₄, filtered and concentrated to give a yellow oil. Purificationby normal phase chromatography gave ethyl1-[4-chloro-2-(6-methoxypyrimidin-4-yl)phenyl]-1H-1,2,3-triazole-4-carboxylate(0.507 g, 83% yield) as a yellow solid. MS(ESI) m/z: 360.0 (M+H)⁺. ¹HNMR (400 MHz, CDCl₃) δ 8.65 (d, J=1.1 Hz, 1H), 8.19 (s, 1H), 7.75 (d,J=2.4 Hz, 1H), 7.62 (dd, J=8.4, 2.4 Hz, 1H), 7.50 (d, J=8.4 Hz, 1H),6.56 (d, J=1.1 Hz, 1H), 4.44 (q, J=7.3 Hz, 2H), 3.96 (s, 3H), 1.42 (t,J=7.2 Hz, 3H).

373B. Preparation of ethyl1-[4-chloro-2-(6-hydroxypyrimidin-4-yl)phenyl]-1H-1,2,3-triazole-4-carboxylate

To a suspension of ethyl1-[4-chloro-2-(6-methoxypyrimidin-4-yl)phenyl]-1H-1,2,3-triazole-4-carboxylate(0.200 g, 0.56 mmol) in CH₃CN (3 mL) was added TMS-I (0.38 mL, 2.78mmol). The resulting clear yellow solution was heated at 50° C. overnight. The reaction was cooled to rt and then it was poured into amixture of 10% sodium thiosulfate and saturated aqueous NaHCO₃. Thereaction was extracted with DCM (3×). The organic layers were combinedand concentrated. Purification by normal phase chromatography gave ethyl1-[4-chloro-2-(6-hydroxypyrimidin-4-yl)phenyl]-1H-1,2,3-triazole-4-carboxylate(0.098 g, 51% yield) as a white solid. MS(ESI) m/z: 345.9 (M+H)⁺. ¹H NMR(400 MHz, CDCl₃) δ 8.30 (s, 1H), 7.97 (d, J=1.1 Hz, 1H), 7.73 (d, J=2.2Hz, 1H), 7.62 (dd, J=8.5, 2.3 Hz, 1H), 7.49 (d, J=8.4 Hz, 1H), 6.46 (d,J=0.9 Hz, 1H), 4.44 (q, J=7.3 Hz, 2H), 1.42 (t, J=7.2 Hz, 3H).

373C. Preparation of ethyl1-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)-1H-1,2,3-triazole-4-carboxylatetrifluoroacetate

To a 1-dram vial containing a white suspension of ethyl1-[4-chloro-2-(6-hydroxypyrimidin-4-yl)phenyl]-1H-1,2,3-triazole-4-carboxylate(0.035 g, 0.10 mmol) and HATU (0.050 g, 0.13 mmol) in CH₃CN (1.0 mL) wasadded DBU (0.023 mL, 0.15 mmol). The resulting clear, yellow solutionwas stirred at rt for 20 min. Then a clear, purple solution of(9R,13S)-13-amino-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(0.030 g, 0.10 mmol), prepared as described in Example 365, in DMF (1.0mL) was added. The reaction was stirred at rt. After 3 h, the reactionwas stopped purified directly by reverse phase chromatography whichgave, after concentration and lyophilization, ethyl1-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)-1H-1,2,3-triazole-4-carboxylate,trifluoroacetate (0.0292 g, 39% yield) as an off-white solid. MS(ESI)m/z: 628.4 (M+H)⁺. ¹H NMR (500 MHz, CD₃OD) δ 8.81 (s, 1H), 8.78 (s, 1H),8.70 (d, J=5.2 Hz, 1H), 7.89 (d, J=2.5 Hz, 1H), 7.74 (dd, J=8.5, 2.5 Hz,1H), 7.70-7.65 (m, 2H), 7.52 (dd, J=5.0, 1.7 Hz, 1H), 7.49 (s, 1H), 6.39(s, 1H), 5.99-5.93 (m, 1H), 4.40 (q, J=7.2 Hz, 2H), 4.05 (s, 3H),2.74-2.66 (m, 1H), 2.32-2.23 (m, 1H), 2.11-1.93 (m, 2H), 1.64-1.54 (m,1H), 1.50-1.41 (m, 1H), 1.38 (t, J=7.2 Hz, 3H), 1.00 (d, J=6.9 Hz, 3H),0.73-0.61 (m, 1H). Analytical HPLC (Method A) RT=4.90 min, purity=98.8%.

373D. Preparation of1-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)-1H-1,2,3-triazole-4-carboxylicacid trifluoroacetate

A clear, colorless solution of ethyl1-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)-1H-1,2,3-triazole-4-carboxylatetrifluoroacetate (0.020 g, 0.027 mmol) in MeOH (0.54 mL) and 1.0 M NaOH(0.14 mL, 0.14 mmol) was stirred at rt. After 2 h the reaction wasstopped, neutralized with 1.0 M HCl and then the reaction wasconcentrated to give a white solid. Purification by reverse phasechromatography gave, after concentration and lyophilization,1-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)-1H-1,2,3-triazole-4-carboxylicacid, trifluoroacetate (0.0126 g, 64% yield) as a white solid. MS(ESI)m/z: 600.3 (M+H)⁺. ¹H NMR (500 MHz, CD₃OD) δ 8.78 (s, 1H), 8.73 (s, 1H),8.71 (d, J=5.2 Hz, 1H), 7.89 (d, J=2.2 Hz, 1H), 7.76-7.73 (m, 1H),7.70-7.66 (m, 2H), 7.50 (dd, J=5.1, 1.5 Hz, 1H), 7.49 (s, 1H), 6.40 (s,1H), 6.00-5.94 (m, 1H), 4.05 (s, 3H), 2.74-2.66 (m, 1H), 2.32-2.23 (m,1H), 2.11-1.93 (m, 2H), 1.64-1.54 (m, 1H), 1.51-1.40 (m, 1H), 1.00 (d,J=6.9 Hz, 3H), 0.73-0.61 (m, 1H). Analytical HPLC (Method A) RT=3.37min, purity=100%.

What is claimed is:
 1. A compound of Formula (I):

or a stereoisomer, a tautomer, a pharmaceutically acceptable saltthereof, wherein: ring A is independently selected from 6-membered aryland 5- to 6-membered heterocyclyl, wherein said aryl and heterocyclylare optionally substituted with, where valence allows, one or more R⁴;ring B is 5- to 10-membered heterocyclyl optionally substituted with,where valence allows, one or more R³ or 5- to 10-membered heterocyclylcomprising carbon atoms and 1-4 heteroatoms selected from N, NR^(3c), O,and S(O)_(p) and optionally substituted with, where valence allows, oneor more R³; G¹ is independently selected from C₃₋₁₀ carbocyclyl and 5-to 10-membered heterocyclyl, wherein said carbocyclyl and heterocyclylare optionally substituted with, where valence allows, one or more R⁸; Xis independently selected from C₄₋₈ alkylene and C₄₋₈ alkenylene,wherein said alkylene and alkenylene are substituted with R¹ and R²;alternatively one or more of the carbon atoms of said alkylene andalkenylene may be replaced by O, C═O, S(═O)_(p), S(═O)_(p)NH, and NR¹⁵;Y is independently selected from —CR¹³NH—, —NHC(═O)—, —C(═O)NH—,—S(═O)_(p)NH—, —NHS(═O)_(p)—, and C₁₋₂ alkylene; R¹ and R² areindependently selected from H, D, halogen, haloalkyl, C₁₋₆ alkyl(optionally substituted with R⁶), hydroxyl, and alkoxy optionallysubstituted with R⁶, and C₃₋₆ cycloalkyl optionally substituted with R⁶;optionally, when R¹ and R² are attached to the same carbon atom,together they form an oxo group or C₃₋₆ cycloalkyl; optionally, when R¹and R² are attached to carbon atoms adjacent to each other, togetherthey form a bond or carbocyclyl; optionally, R¹ and R¹⁵ or R² and R¹⁵taken together form a ring; R³ is independently selected from H, NO₂,═O, halogen, haloalkyl, C₁₋₄ alkyl (optionally substituted with R⁶),C₂₋₄ alkenyl (optionally substituted with R⁶), C₂₋₄ alkynyl (optionallysubstituted with R⁶), CN, —(CH₂)_(n)—OR⁵, —(CH₂)_(n)—NR⁵R⁵,—(CH₂)_(n)—C(═O)R⁵, —(CH₂)_(n)—C(═O)OR⁵, —(CH₂)_(n)—NR⁹C(═O)OR⁵,—(CH₂)_(n)—NR⁹C(═O)R⁵, —(CH₂)_(n)—NR⁹C(N—CN)NHR⁵,—(CH₂)_(n)—NR⁹C(NH)NHR⁵, —(CH₂)_(n)—N═CR⁹NR⁵R⁵,—(CH₂)_(n)—NR⁹C(═O)NR⁵R⁵, —(CH₂)_(n)—C(═O)NR⁵R⁵,—(CH₂)_(n)—NR⁹C(═S)NR⁹C(═O)R⁵, —(CH₂)_(n)—S(═O)_(p)R⁵,—(CH₂)_(n)—S(═O)_(p)NR⁵R⁵, —(CH₂)_(n)—NR⁹S(═O)_(p)NR⁵R⁵,—(CH₂)_(n)—NR⁹S(═O)_(p)R⁵, —(CH₂)_(n)—C₃₋₁₀ carbocyclyl and—(CH₂)_(n)-4- to 10-membered heterocyclyl, wherein said carbocyclyl andheterocyclyl are optionally substituted with R⁶; optionally, twoadjacent R³ groups on the heterocyclyl may form a ring optionallysubstituted with R⁶; R^(3c) is independently selected from H, haloalkyl,C₁₋₄ alkyl (optionally substituted with R⁶), —(CH₂)₁₋₂—OH, C(═O)C₁₋₄alkyl, —(CH₂)₀₋₂—C(═O)OH, —C(═O)OC₁₋₄ alkyl, S(═O)_(p)C₁₋₆ alkyl,—(CH₂)_(n)—C₃₋₁₀ carbocyclyl and —(CH₂)_(n)-4- to 10-memberedheterocyclyl, wherein said carbocyclyl and heterocyclyl are optionallysubstituted with R⁶; R⁴ is independently selected from H, OH, NH₂,halogen, CN, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, —CH₂OH, —C(═O)OH,—CH₂C(═O)OH, —CO₂(C₁₋₄ alkyl), —C(═O)NH₂, —C(═O)NH(C₁₋₄ alkyl),—C(═O)N(C₁₋₄ alkyl)₂, —S(═O)₂C₁₋₄ alkyl, —S(═O)₂NH₂, C₃₋₆ cycloalkyl,aryl, and 5- to 6-membered heterocyclyl, wherein said cycloalkyl, aryland heterocyclyl are optionally substituted with R⁶; R⁵ is independentlyselected from H, C₁₋₄ alkyl (optionally substituted with halogen,hydroxyl, alkoxy, carboxy, hydroxycarbonyl, alkoxycarbonyl, amino,substituted amino), —(CH₂)_(n)—C₃₋₁₀ carbocyclyl and —(CH₂)_(n)-4- to10-membered heterocyclyl, wherein said carbocyclyl and heterocyclyl areoptionally substituted with R⁶; alternatively, R⁵ and R⁵ together withthe nitrogen atom to which they are both attached form a heterocyclicring optionally substituted with R⁶; R⁶ is independently selected fromH, —(CH₂)_(n)—OH, ═O, —(CH₂)_(n)NH₂, —(CH₂)_(n)CN, halogen, C₁₋₆ alkyl,—(CH₂)_(n)—C(═O)OH, —(CH₂)_(n)—C(═O)NH₂, —(CH₂)_(n)—C(═O)OC₁₋₄ alkyl,—(CH₂)_(n)—OC₁₋₄ alkyl, —(CH₂)_(n)—C₃₋₁₀ carbocyclyl, —(CH₂)_(n)-4- to10-membered heterocyclyl, and —O-4- to 10-membered heterocyclyl, whereinsaid carbocyclyl and heterocyclyl are optionally substituted with R¹⁰;R⁷ is independently selected from H, hydroxyl, alkoxy, halogen, amino,C₁₋₃haloalkyl, and C₁₋₃ alkyl; R⁸ is independently selected from H,halogen, —(CH₂)_(n)CN, C₁₋₆ alkyl, amino, aminoalkyl, haloalkyl,hydroxyl, alkoxy, haloalkoxy, alkylcarbonyl, carboxyl, carboxyl ester,amide, haloalkylaminocarbonyl, arylalkylaminocarbonyl,haloalkylaminocarbonyl, alkoxycarbonylamino, haloalkylcarbonylamino,arylamino, heteroarylamino, arylalkylcarbonyl, aryloxy, heteroaryloxy,alkylthio, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, sulfonamide,—(CH₂)_(n)-aryl, —(CH₂)_(n)—C₃₋₆ cycloalkyl, and —(CH₂)_(n)-4- to12-membered heterocyclyl, wherein said aryl, cycloalkyl, andheterocyclyl are optionally substituted with R¹⁰; alternatively, twoadjacent R⁸ groups taken together form a heterocyclic ring optionallysubstituted with R¹⁰; R⁹ is H or C₁₋₆ alkyl; R¹⁰ is independentlyselected from H, C₁₋₆ alkyl (optionally substituted with R¹¹), C₂₋₆alkenyl, C₂₋₆ alkynyl, aryl (optionally substituted with R¹¹),—(CH₂)_(n)—C₃₋₆ cycloalkyl (optionally substituted with R¹¹),—(CH₂)_(n)—O-4- to 10-membered heterocyclyl (optionally substituted withR¹¹), halogen, —(CH₂)_(n)CN, NO₂, ═O, C(═O)NR¹²R¹², —(CH₂)_(n)C(═O)OR¹²,Si(C₁₋₄ alkyl)₃, —(CH₂)_(n)—OR¹², —(CH₂)_(n)—NR¹²R¹², —S(═O)_(p)C₁₋₆alkyl, NR¹²S(═O)_(p)C₁₋₆ alkyl, S(═O)_(p)NR¹²R¹², and C(═NOH)NH₂; R¹¹,at each occurrence, is independently selected from H, halogen, C₁₋₅alkyl, —(CH₂)_(n)—OH, C₃₋₆ cycloalkyl, phenyl, and heterocyclyl; R¹², ateach occurrence, is independently selected from H, C₁₋₅ alkyl optionallysubstituted with R¹¹, C₃₋₆ cycloalkyl, phenyl, and heterocyclyl, or R¹²and R¹² together with the nitrogen atom to which they are both attachedform a heterocyclic ring optionally substituted with C₁₋₄alkyl; R¹³ is,independently at each occurrence, selected from H, C₁₋₄ haloalkyl, C₁₋₄alkyl, C(═O)OH, C(═O)O(C₁₋₄ alkyl), C(═O)O(CH₂)₂O(C₁₋₄ alkyl),C(═O)O(C₁₋₄ haloalkyl), CH₂C(═O)OH, CH₂C(═O)O(C₁₋₄ alkyl), C(═O)NH₂,C(═O)NH(C₁₋₄ alkyl), C(═O)N(C₁₋₄ alkyl)₂, and —C(═O)NH(C₁₋₄ alkoxy); R¹⁵is H or C₁₋₆ alkyl; n, at each occurrence, is an integer independentlyselected from 0, 1, 2, 3, and 4; and p, at each occurrence, is aninteger independently selected from 0, 1, and
 2. 2. The compound ofclaim 1 having Formula (IIa):

or a stereoisomer, a tautomer, a pharmaceutically acceptable saltthereof, wherein: ring A is independently selected from 6-membered aryland 5- to 6-membered heterocyclyl; ring B is 5- to 10-memberedheterocyclyl or 5- to 10-membered heterocyclyl comprising carbon atomsand 1-4 heteroatoms selected from N, NR^(3c), O, and S(O)_(p); G¹ isindependently selected from C₃₋₆ carbocyclyl and 5- to 10-memberedheterocyclyl, wherein said carbocyclyl and heterocyclyl are substitutedwith 1-4 R⁸; W is independently selected from (CR¹R²)₁₋₂, O, NH, andN(C₁₋₄ alkyl); Y is independently selected from —CR¹³NH—, —NHC(═O)— and—C(═O)NH—; R¹ and R² are independently selected from H, halogen,haloalkyl, C₁₋₄ alkyl (optionally substituted with R⁶), hydroxyl, andalkoxy (optionally substituted with R⁶), and C₃₋₅ cycloalkyl optionallysubstituted with R⁶; R³ is independently selected from H, halogen, C₁₋₄alkyl (optionally substituted with R⁶), CN, —(CH₂)_(n)—OR⁵,—(CH₂)_(n)—NR⁵R⁵, —(CH₂)_(n)—C(═O)R⁵, and —(CH₂)_(n)—C(═O)OR⁵; R^(3c) isindependently selected from H, haloalkyl, C₁₋₄ alkyl (optionallysubstituted with R⁶), —(CH₂)₀₋₂—OH, C(═O)C₁₋₄ alkyl, —(CH₂)₀₋₂—C(═O)OH,—C(═O)OC₁₋₄ alkyl, S(═O)_(p)C₁₋₆ alkyl, —(CH₂)_(n)—C₃₋₁₀ carbocyclyl and—(CH₂)_(n)-4- to 10-membered heterocyclyl, wherein said carbocyclyl andheterocyclyl are optionally substituted with R⁶; R⁴ is independentlyselected from H, OH, halogen, CN, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄alkoxy, —C(═O)NH₂, —C(═O)NH(C₁₋₄ alkyl), —C(═O)N(C₁₋₄ alkyl)₂, C₃₋₆cycloalkyl, aryl, and 5- to 6-membered heterocyclyl, wherein saidcycloalkyl, aryl and heterocyclyl are optionally substituted with R⁶; R⁵is independently selected from H, C₁₋₄ alkyl (optionally substitutedwith halogen, hydroxyl, alkoxy, carboxy, alkoxycarbonyl, amino,substituted amino), C₃₋₁₀ carbocyclyl and 4- to 10-memberedheterocyclyl, wherein said carbocyclyl and heterocyclyl are optionallysubstituted with R⁶; R⁶ is independently selected from H, OH, ═O,—(CH₂)_(n)NH₂, —(CH₂)_(n)CN, halogen, C₁₋₆ alkyl, —(CH₂)_(n)—C(═O)OH,—(CH₂)_(n)—C(═O)OC₁₋₄ alkyl, —(CH₂)_(n)—OC₁₋₄ alkyl, —(CH₂)_(n)—C(═O)NH₂, —(CH₂)_(n)—C₃₋₁₀ carbocyclyl, —(CH₂)_(n)-4- to 10-memberedheterocyclyl, and —(CH₂)_(n)-4- to 10-membered heterocyclyl, whereinsaid carbocyclyl and heterocyclyl are optionally substituted with R¹⁰;R⁷ is independently selected from H, hydroxyl, halogen, C₁₋₂haloalkyl,and C₁₋₂alkyl; R⁸ is independently selected from H, halogen, CN, NH₂,C₁₋₆ alkyl, haloalkyl, haloalkylcarbonylamino, arylamino,heteroarylamino, hydroxycarbonyl, haloalkylaminocarbonyl,arylalkylcarbonyl, alkylcarbonyl, alkoxy, haloalkoxy, —(CH₂)_(n)-aryl,—(CH₂)_(n)—C₃₋₆ cycloalkyl, and —(CH₂)_(n)-4- to 12-memberedheterocyclyl, wherein said aryl, cycloalkyl, and heterocyclyl areoptionally substituted with R¹⁰; alternatively, two adjacent R⁸ groupsand G₁ form a fused heterocyclic group selected from

R⁹ is H or C₁₋₆ alkyl; R¹⁰ is independently selected from H, C₁₋₆ alkyl(optionally substituted with R¹¹), C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl(optionally substituted with R¹¹), —(CH₂)_(n)—C₃₋₆ cycloalkyl(optionally substituted with R¹¹), —(CH₂)_(n)—O-4- to 10-memberedheterocyclyl (optionally substituted with R¹¹), F, Cl, Br, —(CH₂)_(n)CN,NO₂, ═O, C(═O)NR¹²R¹², —(CH₂)_(n)C(═O)OR¹², Si(C₁₋₄ alkyl)₃,—(CH₂)_(n)—OR¹², —(CH₂)_(n)—NR¹²R¹², and —S(═O)_(p)Cl-6 alkyl,NR¹²S(═O)_(p)C₁₋₆ alkyl, and S(═O)_(p)NR¹²R¹²; R^(10′) is independentlyselected from H, C₁₋₆ alkyl (optionally substituted with R¹¹), aryl,—(CH₂)_(n)—C₃₋₆ cycloalkyl (optionally substituted with R¹¹), and—(CH₂)_(n)—O-4- to 10-membered heterocyclyl (optionally substituted withR¹¹); R¹¹, at each occurrence, is independently selected from H,halogen, C₁₋₅ alkyl, —(CH₂)_(n)—OH, C₃₋₆ cycloalkyl, and phenyl; R¹², ateach occurrence, is independently selected from H, C₁₋₅ alkyl optionallysubstituted with R¹¹, C₃₋₆ cycloalkyl, phenyl, and heterocyclyl, or R¹²and R¹² together with the nitrogen atom to which they are both attachedform a heterocyclic ring optionally substituted with C₁₋₄alkyl; R¹³ is,independently at each occurrence, selected from H, CF₃, C(═O)OH,C(═O)O(C₁₋₄ alkyl), and —C(═O)NH₂(C₁₋₄ alkoxy); n, at each occurrence,is an integer independently selected from 0, 1, 2, 3, and 4; and p, ateach occurrence, is an integer independently selected from 0, 1, and 2.3. The compound of claim 2 having Formula (IIb):

or a stereoisomer, a tautomer, a pharmaceutically acceptable saltthereof, wherein: ring A is independently selected from phenyl and 5- to6-membered heterocyclyl; ring B is 5- to 10-membered heterocyclyl or 5-to 6-membered heterocyclyl comprising carbon atoms and 1-4 heteroatomsselected from N, NR^(3c), O, and S(O)_(p); W is independently selectedfrom (CR¹R²)₁₋₂, O, NH, and N(C₁₋₄ alkyl); Y is independently selectedfrom —CH₂NH—, —NHC(═O)— and —C(═O)NH—; G³ is independently selected fromN and CR^(8a); G⁴ is independently selected from N and CR^(8e); R¹ andR² are independently selected from H, D, halogen, CF₃, C₁₋₆ alkyl, andhydroxyl; R³ is independently selected from H, halogen, C₁₋₄alkyl(optionally substituted with R⁶), CN, —(CH₂)_(n)—OR⁵, —(CH₂)_(n)—NR⁵R⁵,—(CH₂)_(n)—C(═O)R⁵, and —(CH₂)_(n)—C(═O)OR⁵; R^(3c) is independentlyselected from H, haloalkyl, C₁₋₄ alkyl (optionally substituted with R⁶),—(CH₂)₁₋₂—OH, C(═O)C₁₋₄ alkyl, —(CH₂)₁₋₂—C(═O)OH, —C(═O)OC₁₋₄ alkyl,S(═O)_(p)C₁₋₆ alkyl, —(CH₂)_(n)—C₃₋₁₀ carbocyclyl and —(CH₂)_(n)-4- to10-membered heterocyclyl, wherein said carbocyclyl and heterocyclyl areoptionally substituted with R⁶; R⁴ is independently selected from H, OH,F, Cl, Br, C₁₋₄ alkyl, C₁₋₄ alkoxy, CF₃, CN, C(═O)NH₂, C₃₋₆ cycloalkyl,aryl, and 5- to 6-membered heterocyclyl, wherein said cycloalkyl, aryland heterocyclyl are optionally substituted with R⁶; R⁵ is independentlyselected from H, and C₁₋₄ alkyl optionally substituted with halogen andhydroxyl; R⁶ is independently selected from H, —(CH₂)_(n)—OH, ═O, NH₂,—(CH₂)_(n)—CN, halogen, C₁₋₆ alkyl, —(CH₂)_(n)—C(═O)OH,—(CH₂)_(n)—C(═O)OC₁₋₄ alkyl, —(CH₂)_(n)—OC₁₋₄ alkyl, —(CH₂)_(n)—C₃₋₆cycloalkyl, —(CH₂)_(n)-4- to 10-membered heterocyclyl, and—O—(CH₂)_(n)-4- to 10-membered heterocyclyl, wherein said cycloalkyl andheterocyclyl are optionally substituted with R¹⁰; R⁷ is independentlyselected from H, F, Cl, Br, CF₃, and CH₃; R^(8a) is independentlyselected from H, F, Cl, Br, I, —(CH₂)_(n)CN, —(CH₂)_(n)NH₂, C₁₋₂alkyl,C₁₋₂haloalkyl, OH, OC₁₋₂alkyl, OC₁₋₂haloalkyl, C(═O)OH, C(═O)OC₁₋₃alkyl,C(═O)NH₂, C(═O)NHC₁₋₂haloalkyl, C(═O)NHarylalkyl, C(═O)C₁₋₃alkyl,NHC(═O)OC₁₋₂alkyl, NHC(═O)C₁₋₂haloalkyl, NH-aryl, NH-heteroaryl, aryl,C₃₋₆ cycloalkyl, and 4- to 12-membered heterocyclyl, wherein said aryl,cycloalkyl and heterocyclyl is optionally substituted with R¹⁰; R^(8b)is independently selected from H and F; R^(8c) is independently selectedfrom H, F, Cl, methyl, ethyl, isopropyl, OCHF₂, and OCH₃; R^(8d) isindependently selected from H, F, and C₁; R^(8e) is independentlyselected from H, F, and C₁; R¹⁰ is independently selected from H, C₁₋₆alkyl (optionally substituted with R¹¹), C₂₋₆ alkenyl, C₂₋₆ alkynyl,aryl (optionally substituted with R¹¹), —(CH₂)_(n)—C₃₋₆ cycloalkyl(optionally substituted with R¹¹), —(CH₂)_(n)—O-4- to 10-memberedheterocyclyl (optionally substituted with R¹¹), F, Cl, Br, CN, NO₂, ═O,CONR¹²R¹², —(CH₂)_(n)C(═O)OR¹², Si(C₁₋₄ alkyl)₃, —(CH₂)_(n)—OR¹², and—(CH₂)_(n)—NR¹²R¹², —S(═O)_(p)C₁₋₆ alkyl, NR¹²S(═O)_(p)C₁₋₆ alkyl, andS(═O)_(p)NR¹²R¹²; R¹¹, at each occurrence, is independently selectedfrom H, halogen, C₁₋₅ alkyl, —(CH₂)_(n)—OH, C₃₋₆ cycloalkyl, and phenyl;R¹², at each occurrence, is independently selected from H, C₁₋₅ alkyloptionally substituted with R¹¹, C₃₋₆ cycloalkyl, phenyl, andheterocyclyl, or R¹² and R¹² together with the nitrogen atom to whichthey are both attached form a heterocyclic ring optionally substitutedwith C₁₋₄alkyl; n, at each occurrence, is an integer independentlyselected from 0, 1, and 2; and p, at each occurrence, is an integerindependently selected from 0, 1, and
 2. 4. The compound of claim 3 or astereoisomer, a tautomer, a pharmaceutically acceptable salt thereof,wherein: ring A is independently selected from phenyl and 5- to6-membered heterocyclyl; ring B is 5- to 6-membered heteroarylcomprising carbon atoms and 1-4 heteroatoms selected from N and NR^(3c);W is independently selected from (CR¹R²)₁₋₂, O, NH, and N(C₁₋₄ alkyl); Yis independently selected from —CH₂NH—, —NHC(═O)— and —C(═O)NH—; G³ isCR^(8a); G⁴ is CR^(8e); R¹ and R² are independently selected from H, D,halogen, CF₃, C₁₋₆ alkyl, and hydroxyl; R³ is independently selectedfrom H, halogen, C₁₋₄alkyl (optionally substituted with R⁶), CN,—(CH₂)_(n)—OR⁵, —(CH₂)_(n)—C(═O)R⁵, and —(CH₂)_(n)—C(═O)OR⁵; R^(3c) isindependently selected from H, haloalkyl, C₁₋₄ alkyl (optionallysubstituted with R⁶), —(CH₂)₁₋₂—OH, C(═O)C₁₋₄ alkyl, —(CH₂)₁₋₂—C(═O)OH,—C(═O)OC₁₋₄ alkyl, S(═O)_(p)C₁₋₆ alkyl, —(CH₂)_(n)—C₃₋₁₀ carbocyclyl and—(CH₂)_(n)-4- to 10-membered heterocyclyl, wherein said carbocyclyl andheterocyclyl are optionally substituted with R⁶; R⁴ is independentlyselected from H, OH, F, Cl, Br, C₁₋₄ alkyl, C₁₋₄ alkoxy, CF₃, CN,C(═O)NH₂, C₃₋₆ cycloalkyl, aryl, and 5- to 6-membered heterocyclyl,wherein said cycloalkyl, aryl and heterocyclyl are optionallysubstituted with R⁶; R⁵ is independently selected from H and C₁₋₄ alkyl;R⁶ is independently selected from H, —(CH₂)_(n)—OH, ═O, NH₂,—(CH₂)_(n)—CN, halogen, C₁₋₆ alkyl, —(CH₂)_(n)—C(═O)OH,—(CH₂)_(n)—C(═O)OC₁₋₄ alkyl, —(CH₂)_(n)—OC₁₋₄ alkyl, —(CH₂)_(n)—C₃₋₆cycloalkyl, —(CH₂)_(n)-4- to 10-membered heterocyclyl, and—O—(CH₂)_(n)-4- to 10-membered heterocyclyl, wherein said cycloalkyl andheterocyclyl are optionally substituted with R¹⁰; R⁷ is independentlyselected from H, F, Cl, Br, and methyl; R^(8a) is independently selectedfrom H, F, Cl, Br, I, —(CH₂)_(n)CN, —(CH₂)_(n)NH₂, CH₃CHF₂, CCH₃F₂, CF₃,OH, OCH₃, OCF₃, OCHF₂, C(═O)CH₃, C(═O)OH, C(═O)OCH₃, C(═O)NH₂,C(═O)NHCH₂CF₃, C(═O)NHCH₂Ph, NHC(═O)OCH₃, NHC(═O)CF₃,

R^(8b) is independently selected from H and F; R^(8c) is independentlyselected from H, F, Cl, methyl, ethyl, isopropyl, and OCH₃; R^(8d) isindependently selected from H, F, and C₁; R^(8e) is independentlyselected from H, F, and C₁; R¹⁰ is independently selected from H, C₁₋₆alkyl (optionally substituted with R¹¹), C₂₋₆ alkenyl, C₂₋₆ alkynyl,aryl (optionally substituted with R¹¹), —(CH₂)_(n)—C₃₋₆ cycloalkyl(optionally substituted with R¹¹), —(CH₂)_(n)—O-4- to 10-memberedheterocyclyl (optionally substituted with R¹¹), F, Cl, Br, CN, NO₂, ═O,CONR¹²R¹², —(CH₂)_(n)—C(═O)OR¹², Si(C₁₋₄ alkyl)₃, —(CH₂)_(n)—OR¹²,—(CH₂)_(n)—NR¹²R¹², —S(═O)_(p)C₁₋₆ alkyl, NR¹²S(═O)_(p)C₁₋₆ alkyl, andS(═O)_(p)NR¹²R¹²; R^(10′) is independently selected from H, C₁₋₆ alkyl(optionally substituted with R¹¹), aryl, —(CH₂)_(n)—C₃₋₆ cycloalkyl(optionally substituted with R¹¹), and —(CH₂)_(n)—O-4- to 10-memberedheterocyclyl (optionally substituted with R¹¹); R¹¹, at each occurrence,is independently selected from H, halogen, C₁₋₅ alkyl, —(CH₂)_(n)—OH,C₃₋₆ cycloalkyl, and phenyl; R¹², at each occurrence, is independentlyselected from H, C₁₋₅ alkyl optionally substituted with R¹¹, C₃₋₆cycloalkyl, phenyl, and heterocyclyl, or R¹² and R¹² together with thenitrogen atom to which they are both attached form a heterocyclic ringoptionally substituted with C₁₋₄alkyl; n, at each occurrence, is aninteger independently selected from 0, 1, and 2; and p, at eachoccurrence, is an integer independently selected from 0, 1, and
 2. 5.The compound of claim 4 having Formula (IIc):

or a stereoisomer, a tautomer, a pharmaceutically acceptable saltthereof, wherein: ring A is independently selected from phenyl and 5- to6-membered heterocyclyl; ring B is 5- to 6-membered heteroarylcomprising carbon atoms and 1-3 heteroatoms selected from N and NR^(3c);W is independently selected from (CR¹R²)₁₋₂, O, NH, and N(C₁₋₄ alkyl); Yis independently selected from —CH₂NH—, —NHC(═O)— and —C(═O)NH—; R¹ andR² are independently selected from H, D, F, C₁₋₄ alkyl, and hydroxyl; R³is independently selected from H, halogen, haloalkyl, C₁₋₄alkyl(optionally substituted with R⁶), and CN; R^(3c) is independentlyselected from H, haloalkyl, C₁₋₄ alkyl (optionally substituted with R⁶),—(CH₂)₁₋₂—OH, C(═O)C₁₋₄ alkyl, —(CH₂)₁₋₂—C(═O)OH, —C(═O)OC₁₋₄ alkyl,S(═O)_(p)C₁₋₆ alkyl, —(CH₂)_(n)—C₃₋₁₀ carbocyclyl and —(CH₂)_(n)-4- to10-membered heterocyclyl, wherein said carbocyclyl and heterocyclyl areoptionally substituted with R⁶; R⁴ is independently selected from H, OH,F, Cl, Br, C₁₋₄ alkyl, C₁₋₄ alkoxy, CF₃, CN; C(═O)NH₂, C₃₋₆ cycloalkyl,aryl, and 5- to 6-membered heterocyclyl; R⁶ is independently selectedfrom H, —(CH₂)_(n)—OH, ═O, NH₂, —(CH₂)_(n)—CN, halogen, C₁₋₆ alkyl,—(CH₂)_(n)—C(═O)OH, —(CH₂)_(n)—C(═O)OC₁₋₄ alkyl, —(CH₂)_(n)—OC₁₋₄ alkyl,—(CH₂)_(n)—C₃₋₆ cycloalkyl, —(CH₂)_(n)-4- to 10-membered heterocyclyl,and —O—(CH₂)_(n)-4- to 10-membered heterocyclyl, wherein said cycloalkyland heterocyclyl are optionally substituted with R¹⁰; R^(8b) isindependently selected from H and F; R^(8c) is independently selectedfrom H, F, Cl, CH₃, and OCH₃; R¹⁰ is independently selected from H, C₁₋₆alkyl (optionally substituted with R¹¹), C₂₋₆ alkenyl, C₂₋₆ alkynyl,aryl, —(CH₂)_(n)—C₃₋₆ cycloalkyl (optionally substituted with R¹¹),—(CH₂)_(n)—O-4- to 10-membered heterocyclyl (optionally substituted withR¹¹), F, Cl, Br, CN, NO₂, ═O, C(═O)NR¹²R¹², C(═O)OR¹², Si(C₁₋₄ alkyl)₃,—(CH₂)_(n)—OR¹², —(CH₂)_(n)—NR¹²R¹², —S(═O)_(p)C₁₋₆ alkyl,NR¹²S(═O)_(p)C₁₋₆ alkyl, and S(═O)_(p)NR¹²R¹²; R¹¹, at each occurrence,is independently selected from H, halogen, C₁₋₅ alkyl, —(CH₂)_(n)—OH,C₃₋₆ cycloalkyl, and phenyl; R¹², at each occurrence, is independentlyselected from H, C₁₋₅ alkyl, C₃₋₆ cycloalkyl, phenyl, and heterocyclyl,or R¹² and R¹² together with the nitrogen atom to which they are bothattached form a heterocyclic ring optionally substituted with C₁₋₄alkyl;n, at each occurrence, is an integer independently selected from 0, 1,and 2; and p, at each occurrence, is an integer independently selectedfrom 0, 1, and
 2. 6. The compound of claim 5 having Formula (IId):

or a stereoisomer, a tautomer, a pharmaceutically acceptable saltthereof, wherein:

is an optional bond; ring A is independently selected from phenyl and 5-to 6-membered heterocyclyl; W is independently selected from CHR^(1a),O, NH, and N(C₁₋₄ alkyl); G⁵ is independently selected from CH₂ andNR³C; G⁶ is independently selected from CH₂ and NR³C; provided when G⁵is CH₂, G⁶ is NR³C; when G⁵ is NR^(3c), G⁶ is CH₂ and only one R^(3c) ispresent on the ring; Y is independently selected from —NHC(═O)— and—C(═O)NH—; R¹ is independently selected from H and C₁₋₄ alkyl; R^(1a) isindependently selected from H, D, F, CH₃, and OH; R² is independentlyselected from H, D, and OH; R^(3c) is independently selected from H,haloalkyl, C₁₋₄alkyl (optionally substituted with R⁶), —(CH₂)₀₋₂—OH,C(═O)C₁₋₄ alkyl, —(CH₂)₀₋₂—C(═O)OH, —C(═O)OC₁₋₄ alkyl, S(═O)_(p)C₁₋₆alkyl, phenyl optionally substituted with R⁶, 5- to 6-memberedheterocyclyl optionally substituted with R⁶, and 5- to 6-memberedheteroaryl optionally substituted with R⁶; R⁴ is independently selectedfrom H, OH, F, Cl, Br, C₁₋₄ alkyl, C₁₋₄ alkoxy, CF₃, CN, and C(═O)NH₂;R⁶ is independently selected from H, —(CH₂)_(n)—OH, ═O, NH₂,—(CH₂)_(n)—CN, halogen, C₁₋₆ alkyl, —(CH₂)_(n)—C(═O)OH,—(CH₂)_(n)—C(═O)OC₁₋₄ alkyl, —(CH₂)_(n)—OC₁₋₄ alkyl, —(CH₂)_(n)—C₃₋₆cycloalkyl, —(CH₂)_(n)-4- to 10-membered heterocyclyl, and—O—(CH₂)_(n)-4- to 10-membered heterocyclyl, wherein said cycloalkyl andheterocyclyl are optionally substituted with R¹⁰; R^(8b) isindependently selected from H and F; R^(8c) is independently selectedfrom H, F, Cl, CH₃, and OCH₃; R¹⁰ is independently selected from H, C₁₋₆alkyl (optionally substituted with R¹¹), aryl, —(CH₂)_(n)—C₃₋₆cycloalkyl (optionally substituted with R¹¹), —(CH₂)_(n)—O-4- to10-membered heterocyclyl (optionally substituted with R¹¹), F, Cl, Br,CN, NO₂, ═O, C(═O)NR¹²R¹², C(═O)OR¹², Si(C₁₋₄ alkyl)₃, —(CH₂)_(n)—OR¹²,—(CH₂)_(n)—NR¹²R¹², —S(═O)_(p)C₁₋₆ alkyl, NR¹²S(═O)_(p)C₁₋₆ alkyl, andS(═O)_(p)NR¹²R¹²; R¹¹, at each occurrence, is independently selectedfrom H, halogen, C₁₋₅ alkyl, —(CH₂)_(n)—OH, C₃₋₆ cycloalkyl, and phenyl;R¹², at each occurrence, is independently selected from H, C₁₋₅ alkyl,C₃₋₆ cycloalkyl, phenyl, and heterocyclyl, or R¹² and R¹² together withthe nitrogen atom to which they are both attached form a heterocyclicring optionally substituted with C₁₋₄alkyl; n, at each occurrence, is aninteger independently selected from 0, 1, and 2; and p, at eachoccurrence, is an integer independently selected from 0, 1, and
 2. 7.The compound of claim 6 having Formula (IIe):

or a stereoisomer, a tautomer, a pharmaceutically acceptable saltthereof, wherein: ring A is independently selected from

R¹ is independently selected from H and C₁₋₄ alkyl; R^(1a) isindependently selected from H, D, F, CH₃, and OH; R² is independentlyselected from H, D, and OH; R^(3c) is independently selected from H,CHF₂, CD₃, CH₃, CH₂CH₂OH, CH₂C(═O)OH, SO₂CH₃, phenyl optionallysubstituted with R⁶, and 5- to 6-membered heteroaryl optionallysubstituted with R⁶; R⁴ is independently selected from H, F, andC(═O)NH₂; R⁶ is independently selected from H, —(CH₂)_(n)—OH, ═O, NH₂,—(CH₂)_(n)—CN, halogen, C₁₋₆ alkyl, —(CH₂)_(n)—C(═O)OH,—(CH₂)_(n)—C(═O)OC₁₋₄ alkyl, —(CH₂)_(n)—OC₁₋₄ alkyl, —(CH₂)_(n)—C₃₋₆cycloalkyl, —(CH₂)_(n)-4- to 10-membered heterocyclyl, and—O—(CH₂)_(n)-4- to 10-membered heterocyclyl, wherein said cycloalkyl andheterocyclyl are optionally substituted with R¹⁰; R^(8b) isindependently selected from H and F; R^(8c) is independently selectedfrom H, F, Cl, CH₃, and OCH₃; R¹⁰ is independently selected from H, CF₃,CHF₂, CH₂F, aryl, —(CH₂)_(n)—C₃₋₆ cycloalkyl (optionally substitutedwith R¹¹), heteroaryl (optionally substituted with R¹¹), —(CH₂)_(n)—O-4-to 10-membered heterocyclyl (optionally substituted with R¹¹), F, Cl,Br, CN, NO₂, ═O, C(═O)NR¹²R¹², —(CH₂)_(n)—C(═O)OR¹², Si(C₁₋₄ alkyl)₃,—(CH₂)_(n)—OR¹², —(CH₂)_(n)—NR¹²R¹², —S(═O)_(p)C₁₋₆ alkyl,NR¹²S(═O)_(p)C₁₋₆ alkyl, and S(═O)_(p)NR¹²R¹²; R¹¹, at each occurrence,is independently selected from H, halogen, C₁₋₅ alkyl, —(CH₂)_(n)—OH,C₃₋₆ cycloalkyl, and phenyl; R¹², at each occurrence, is independentlyselected from H, C₁₋₅ alkyl, C₃₋₆ cycloalkyl, phenyl, and heterocyclyl,or R¹² and R¹² together with the nitrogen atom to which they are bothattached form a heterocyclic ring optionally substituted with C₁₋₄alkyl;and n, at each occurrence, is an integer independently selected from 0,1, and
 2. 8. The compound of claim 6 having Formula (IIf):

or a stereoisomer, a tautomer, a pharmaceutically acceptable saltthereof, wherein: ring A is independently selected from

R¹ is independently selected from H and C₁₋₄ alkyl; R^(1a) isindependently selected from H, D, F, CH₃, and OH; R² is independentlyselected from H, D, and OH; R^(3c) is independently selected from H,CHF₂, CD₃, CH₃, SO₂CH₃, phenyl optionally substituted with R⁶, and 5- to6-membered heterocyclyl optionally substituted with R⁶, 5- to 6-memberedheteroaryl optionally substituted with R⁶; R⁴ is independently selectedfrom H and F; R⁶ is independently selected from OH, ═O, NH₂, CN,halogen, C₁₋₆ alkyl, —(CH₂)_(n)—C₃₋₆ cycloalkyl, —(CH₂)_(n)-4- to10-membered heterocyclyl, and —O—(CH₂)_(n)-4- to 10-memberedheterocyclyl, wherein said cycloalkyl and heterocyclyl are optionallysubstituted with R¹⁰; R^(8b) is independently selected from H and F;R^(8c) is independently selected from H, F, Cl, CH₃, and OCH₃; R¹⁰ isindependently selected from H, CF₃, CHF₂, C(CH₃)₂OH, aryl,—(CH₂)_(n)—C₃₋₆ cycloalkyl (optionally substituted with R¹¹),—(CH₂)_(n)—O-4- to 10-membered heterocyclyl (optionally substituted withR¹¹), F, Cl, Br, CN, NO₂, ═O, C(═O)NR¹²R¹², C(═O)OR¹², Si(C₁₋₄ alkyl)₃,—(CH₂)_(n)—OR¹², —(CH₂)_(n)—NR¹²R¹², —S(═O)_(p)C₁₋₆ alkyl,NR¹²S(═O)_(p)C₁₋₆ alkyl, and S(═O)_(p)NR¹²R¹²; R¹¹, at each occurrence,is independently selected from H, halogen, C₁₋₅ alkyl, —(CH₂)_(n)—OH,C₃₋₆ cycloalkyl, and phenyl; R¹², at each occurrence, is independentlyselected from H, C₁₋₅ alkyl, C₃₋₆ cycloalkyl, phenyl, and heterocyclyl,or R¹² and R¹² together with the nitrogen atom to which they are bothattached form a heterocyclic ring optionally substituted with C₁₋₄alkyl;and n, at each occurrence, is an integer independently selected from 0,1, and
 2. 9. The compound of claim 6 having Formula (IIg):

or a stereoisomer, a tautomer, a pharmaceutically acceptable saltthereof, wherein: ring A is independently selected from

R¹ is independently selected from H and C₁₋₄ alkyl; R^(1a) isindependently selected from H, F, CH₃, and OH; R² is independentlyselected from H and OH; R^(3c) is independently selected from H, CHF₂,CD₃, and CH₃; R⁴ is independently selected from H and F; R^(8b) isindependently selected from H and F; R^(8c) is independently selectedfrom H, F, Cl, CH₃, and OCH₃; R¹⁰ is independently selected from H, CF₃,CHF₂, aryl, —(CH₂)_(n)—C₃₋₆ cycloalkyl (optionally substituted withR¹¹), —(CH₂)_(n)—O-4- to 10-membered heterocyclyl (optionallysubstituted with R¹¹), F, Cl, Br, CN, NO₂, ═O, C(═O)NR¹²R¹², C(═O)OR¹²,Si(C₁₋₄ alkyl)₃, —(CH₂)_(n)—OR¹², —(CH₂)_(n)—NR¹²R¹², —S(═O)_(p)C₁₋₆alkyl, NR¹²S(═O)_(p)C₁₋₆ alkyl, and S(═O)_(p)NR¹²R¹²; R¹¹, at eachoccurrence, is independently selected from H, halogen, C₁₋₅ alkyl,—(CH₂)_(n)—OH, C₃₋₆ cycloalkyl, and phenyl; R¹², at each occurrence, isindependently selected from H, C₁₋₅ alkyl, C₃₋₆ cycloalkyl, phenyl, andheterocyclyl, or R¹² and R¹² together with the nitrogen atom to whichthey are both attached form a heterocyclic ring optionally substitutedwith C₁₋₄alkyl; and n, at each occurrence, is an integer independentlyselected from 0, 1, and
 2. 10. The compound of claim 2 having Formula(IIIb):

or a stereoisomer, a tautomer, a pharmaceutically acceptable saltthereof, wherein: ring A is independently selected from phenyl and 5- to6-membered heterocyclyl; G¹ is independently selected from aryl,C₃₋₆cycloalkyl and 5- to 6-membered heterocyclyl, wherein said aryl,cycloalkyl and heterocyclyl are substituted with 1-4 R⁸; G² isindependently selected from N and CR^(3b); G⁷ is independently selectedfrom N and CR³; G⁸ is independently selected from N and CR³; provided atleast one of G², G⁷, and G⁸ is N; R¹ and R² are independently selectedfrom H, halogen, CF₃, C₁₋₆ alkyl, and hydroxyl; R³ is independentlyselected from H, halogen, haloalkyl, C₁₋₄alkyl (optionally substitutedwith R⁶), C₂₋₄alkenyl (optionally substituted with R⁶), CN, NO₂,—(CH₂)_(n)—OR⁵, —(CH₂)_(n)—NR⁵R⁵, —(CH₂)_(n)—C(═O)OR⁵,—(CH₂)_(n)—NHC(═O)OR⁵, —(CH₂)_(n)—NHC(═O)R⁵, —(CH₂)_(n)—NHC(N—CN)NHR⁵,—(CH₂)_(n)—NHC(NH)NHR, —(CH₂)_(n)—N═CHNR⁵R⁵, —(CH₂)_(n)—NHC(═O)NR⁵R⁵,—(CH₂)_(n)—C(═O)NR⁵R⁵, —(CH₂)_(n)—NHC(S)NR⁹C(═O)R⁵,—(CH₂)_(n)—S(═O)_(p)C₁₋₆ alkyl optionally substituted with R¹¹,—(CH₂)_(n)—S(═O)_(p)NR⁵R⁵, —(CH₂)_(n)—NHS(═O)_(p)NR⁵R⁵,—(CH₂)_(n)—NHS(═O)_(p)C₁₋₆ alkyl optionally substituted with R¹¹,—(CH₂)_(n)—C₃₋₁₀ carbocyclyl and —(CH₂)_(n)-4- to 10-memberedheterocyclyl, wherein said carbocyclyl and heterocyclyl are optionallysubstituted with R⁶; optionally, two adjacent R³ groups on thecarbocyclyl and heterocyclyl may form a ring optionally substituted withR⁶; R^(3a) is independently selected from H and halogen; R^(3b) isindependently selected from H, halogen, methyl, and CN; R⁴ isindependently selected from H, OH, F, Cl, Br, C₁₋₄ alkyl, C₁₋₄ alkoxy,CF₃, CN, C₃₋₆ cycloalkyl, aryl, and 5- to 6-membered heterocyclyl,wherein said cycloalkyl, aryl and heterocyclyl are optionallysubstituted with R⁶; R⁵ is independently selected from H, C₁₋₄ alkyl(optionally substituted with halogen, hydroxyl, alkoxy, carboxy,alkoxycarbonyl, amino, substituted amino), —(CH₂)_(n)—C₃₋₁₀ carbocyclyland —(CH₂)_(n)-4- to 10-membered heterocyclyl, wherein said carbocyclyland heterocyclyl are optionally substituted with R⁶; R⁶ is independentlyselected from —(CH₂)_(n)—OH, ═O, NH₂, —(CH₂)_(n)—CN, halogen, C₁₋₆alkyl, —(CH₂)_(n)—C(═O)OH, —(CH₂)_(n)—C(═O)OC₁₋₄ alkyl, —(CH₂)_(n)—OC₁₋₄alkyl, —(CH₂)_(n)—C₃₋₆ cycloalkyl, —(CH₂)_(n)-4- to 10-memberedheterocyclyl, and —O—(CH₂)_(n)-4- to 10-membered heterocyclyl, whereinsaid cycloalkyl and heterocyclyl are optionally substituted with R¹⁰; R⁷is independently selected from H, F, Cl, and methyl; R⁸ is independentlyselected from H, halogen, CN, NH₂, C₁₋₆ alkyl, haloalkyl, alkylcarbonyl,alkoxy, haloalkoxy, aryl, C₃₋₆ cycloalkyl, and 4- to 12-memberedheterocyclyl, wherein said aryl, cycloalkyl, and heterocyclyl areoptionally substituted with R¹⁰; R¹⁰ is independently selected from H,C₁₋₆ alkyl (optionally substituted with R¹¹), C₂₋₆ alkenyl, C₂₋₆alkynyl, aryl, —(CH₂)_(n)—C₃₋₆ cycloalkyl (optionally substituted withR¹¹), —(CH₂)_(n)—O-4- to 10-membered heterocyclyl (optionallysubstituted with R¹¹), F, Cl, Br, CN, NO₂, ═O, C(═O)NR¹²R¹², C(═O)OR¹²,Si(C₁₋₄ alkyl)₃, —(CH₂)_(n)—OR¹², —(CH₂)_(n)—NR¹²R¹², —S(═O)_(p)C₁₋₆alkyl, NR¹²S(═O)_(p)C₁₋₆ alkyl, and S(═O)_(p)NR¹²R¹²; R¹¹, at eachoccurrence, is independently selected from H, halogen, C₁₋₅ alkyl,—(CH₂)_(n)—OH, C₃₋₆ cycloalkyl, and phenyl; R¹², at each occurrence, isindependently selected from H, C₁₋₅ alkyl, C₃₋₆ cycloalkyl, phenyl, andheterocyclyl, or R¹² and R¹² together with the nitrogen atom to whichthey are both attached form a heterocyclic ring optionally substitutedwith C₁₋₄alkyl; n, at each occurrence, is an integer independentlyselected from 0, 1, and 2; and p, at each occurrence, is an integerindependently selected from 0, 1, and
 2. 11. The compound of claim 10,having Formula (IVa):

or a stereoisomer, a tautomer, a pharmaceutically acceptable saltthereof, wherein: ring A is independently selected from

R¹ and R² are independently selected from H, F, C₁₋₄ alkyl, and OH;R^(1a), at each occurrence, is independently selected from H, F, CH₃,and OH; R³ is independently selected from H, F, Cl, Br, I, C₂₋₄alkenyl(optionally substituted C(═O)OH), CN, and —(CH₂)_(n)—OH; R⁴ isindependently selected from H, OH, F, OC₁₋₄ alkyl, C₁₋₄ alkyl, CN, C₃₋₆cycloalkyl, aryl, and 5- to 6-membered heterocyclyl, wherein saidcycloalkyl, aryl and heterocyclyl are optionally substituted with R⁶; R⁶is independently selected from OH, NH₂, halogen, C₁₋₆ alkyl, C₃₋₆cycloalkyl, —(CH₂)_(n)—C(═O)OH, —(CH₂)_(n)—C(═O)OC₁₋₄ alkyl,—(CH₂)_(n)—OC₁₋₄ alkyl, ═O, C₃₋₆ cycloalkyl, 4- to 10-memberedheterocyclyl, and —O-4- to 10-membered heterocyclyl, wherein saidcycloalkyl and heterocyclyl are optionally substituted with R¹⁰; R^(8a)is independently selected from H, F, Cl, Br, CN, OCH₃, OCF₃, CH₃,C(═O)CH₃, CF₃, OCHF₂, NHC(═O)C₁₋₄ alkyl, aryl, C₃₋₆ cycloalkyl, and 4-to 12-membered heterocyclyl, wherein said aryl, cycloalkyl, andheterocyclyl are optionally substituted with R¹⁰; R^(8b) isindependently selected from H and F; R^(8c) is independently selectedfrom H, F, Cl, CH₃, and OCH₃; R¹⁰ is independently selected from C₁₋₆alkyl, —C₃₋₆ cycloalkyl, F, Cl, Br, CF₃, CHF₂, CN, and OC₁₋₅ alkyl; andn, at each occurrence, is an integer independently selected from 0, 1,and
 2. 12. The compound of claim 3, or a stereoisomer, a tautomer, apharmaceutically acceptable salt thereof, wherein: ring A isindependently selected from

ring B is independently selected from

W is independently selected from CHR^(1a), O, NH, and N(C₁₋₄ alkyl); R¹is independently selected from H and C₁₋₄ alkyl; R^(1a) is independentlyselected from H F, CH₃, and hydroxyl; R² is independently selected fromH and hydroxyl; R³ is independently selected from H, ═O, F, CHF₂, CF₃,OCF₃, OCHF₂, CH₃, CN, —(CH₂)₀₋₂—OH, OC₁₋₄ alkyl, C(═O)C₁₋₄ alkyl,—(CH₂)₀₋₁—C(═O)OH, —C(═O)OC₁₋₄ alkyl, —S(═O)₂C₁₋₄ alkyl, and—NHC(═O)OC₁₋₄ alkyl; R^(3c) is independently selected from H, CF₂H, CF₃,C₁₋₄ alkyl, and CD₃; R⁴ is independently selected from H and F; R^(8b)is independently selected from H and F; R^(8c) is independently selectedfrom H and C₁; R¹⁰ is independently selected from H, C₁₋₆ alkyl(optionally substituted with R¹¹), aryl, —(CH₂)_(n)—C₃₋₆ cycloalkyl(optionally substituted with R¹¹), —(CH₂)_(n)—O-4- to 10-memberedheterocyclyl, F, Cl, Br, CN, C(═O)NR¹²R¹², Si(C₁₋₄ alkyl)₃, and—(CH₂)_(n)—OR¹²; R¹¹, at each occurrence, is independently selected fromH, halogen, and C₁₋₅ alkyl; and n, at each occurrence, is an integerindependently selected from 0, 1, 2, 3, and
 4. 13. The compound of claim2, or a stereoisomer, a tautomer, a pharmaceutically acceptable saltthereof, wherein ring A is independently selected from

ring B is independently selected from

G¹ is independently selected from

W is independently selected from CHR¹, O, NH, and N(C₁₋₄ alkyl); Y isindependently selected from —NH—, —NHC(═O)— and —C(═O)NH—; R¹ and R² areindependently selected from H, F, C₁₋₄ alkyl, and hydroxyl; R³ isindependently selected from H, ═O, F, CHF₂, CF₃, OCF₃, OCHF₂, CH₃, CN,—(CH₂)₀₋₂—OH, OC₁₋₄ alkyl, C(═O)C₁₋₄ alkyl, —(CH₂)₀₋₁—C(═O)OH,—C(═O)OC₁₋₄ alkyl, —S(═O)₂C₁₋₄ alkyl, and —NHC(═O)OC₁₋₄ alkyl; R^(3c) isindependently selected from H, CF₂H, CF₃, C₁₋₄ alkyl, and CD₃; R⁴ isindependently selected from H, F, and C₁₋₄ alkyl; and R⁷ is H.
 14. Thecompound of claim 4 having Formula (V):

or a stereoisomer, a tautomer, a pharmaceutically acceptable saltthereof, wherein: ring A is independently selected from phenyl and 5- to6-membered heterocyclyl; W is independently selected from CHR^(1a), O,NH, and N(C₁₋₄ alkyl); R¹ is independently selected from H and C₁₋₄alkyl; R^(1a) is independently selected from H, F, CH₃, and hydroxyl; R²is independently selected from H and hydroxyl; R³ is independentlyselected from H, haloalkyl, C₁₋₄alkyl (optionally substituted with R⁶),F, CN, C(═O)C₁₋₄ alkyl, C(═O)OH, C(═O)OC₁₋₄ alkyl, —S(═O)₂C₁₋₄alkyl, and—NHC(═O)OC₁₋₄ alkyl; R⁴ is independently selected from H, OH, F, Cl, Br,C₁₋₄ alkyl, C₁₋₄ alkoxy, CF₃, and CN; R⁵ is independently selected fromH, C₁₋₄ alkyl (optionally substituted with halogen, hydroxyl, alkoxy,carboxy, alkoxycarbonyl, amino, substituted amino), —(CH₂)_(n)—C₃₋₁₀carbocyclyl and —(CH₂)_(n)-4- to 10-membered heterocyclyl, wherein saidcarbocyclyl and heterocyclyl are optionally substituted with R⁶; R⁶ isindependently selected from —(CH₂)_(n)—OH, ═O, NH₂, —(CH₂)_(n)—CN,halogen, C₁₋₆ alkyl, —(CH₂)_(n)—C(═O)OH, —(CH₂)_(n)—C(═O)OC₁₋₄ alkyl,—(CH₂)_(n)—OC₁₋₄ alkyl, —(CH₂)_(n)—C₃₋₆ cycloalkyl, —(CH₂)_(n)-4- to10-membered heterocyclyl, and —O—(CH₂)_(n)-4- to 10-memberedheterocyclyl, wherein said cycloalkyl and heterocyclyl are optionallysubstituted with R¹⁰; R⁷ is independently selected from H, F, Cl, andmethyl; R^(8b) is independently selected from H and F; R^(8c) isindependently selected from H, F, Cl, CH₃, and OCH₃; R¹⁰ isindependently selected from H, C₁₋₆ alkyl (optionally substituted withR¹¹), C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, —(CH₂)_(n)—C₃₋₆ cycloalkyl(optionally substituted with R¹¹), —(CH₂)_(n)—O-4- to 10-memberedheterocyclyl (optionally substituted with R¹¹), F, Cl, Br, CN, NO₂, ═O,C(═O)NR¹²R¹², C(═O)OR¹², Si(C₁₋₄ alkyl)₃, —(CH₂)_(n)—OR¹², and—(CH₂)_(n)—NR¹²R¹²; R¹¹, at each occurrence, is independently selectedfrom H, halogen, C₁₋₅ alkyl, —(CH₂)_(n)—OH, C₃₋₆ cycloalkyl, and phenyl;R¹², at each occurrence, is independently selected from H, C₁₋₅ alkyl,C₃₋₆ cycloalkyl, phenyl, and heterocyclyl, or R¹² and R¹² together withthe nitrogen atom to which they are both attached form a heterocyclicring optionally substituted with C₁₋₄alkyl; n, at each occurrence, is aninteger independently selected from 0, 1, and 2; and p, at eachoccurrence, is an integer independently selected from 0, 1, and
 2. 15. Apharmaceutical composition comprising one or more compounds according toclaim 1 and a pharmaceutically acceptable carrier or diluent.
 16. Amethod for the treatment and/or prophylaxis of a venous cardiovascularthromboembolic disorder comprising: administering to a patient in needthereof a therapeutically effective amount of a compound of Formula(VII):

or a pharmaceutically acceptable salt thereof, wherein: ring A isindependently selected from

ring B is independently selected from

R¹ is independently selected from H and C₁₋₄ alkyl; R¹⁰ is independentlyselected from H, F, Cl, CF₃, CHF₂, and COOH; R^(3c) is independentlyselected from H, CHF₂, CD₃, CH₃, and

R^(8b) is independently selected from H and F; and R^(8c) isindependently selected from H, F, Cl, CH₃, and OCH₃.
 17. The methodaccording to claim 16 wherein the venous cardiovascular thromboembolicdisorder is venous thrombosis.
 18. The method according to claim 16,wherein R¹⁰ in Formula (VII) is independently selected from F, Cl, CF₃,and CHF₂.
 19. The method according to claim 16, wherein the compound hasFormula (VIII):

wherein: R¹ is C₁₋₄ alkyl; R¹⁰ is independently selected from F, Cl,CF₃, CHF₂, and COOH; R^(3c) is independently selected from CHF₂, CD₃,and CH₃; R^(8b) is H; and R^(8c) is independently selected from F andC₁.
 20. The method according to claim 16, wherein the compound hasFormula (IX):

wherein: R¹ is C₁₋₄ alkyl; R¹⁰ is independently selected from F, Cl,CF₃, CHF₂, and COOH; R^(3c) is independently selected from CHF₂, CD₃,and CH₃; R^(8b) is H; and R^(8c) is independently selected from F andCl.
 21. The method according to claim 19, wherein the compound hasFormula (X):

wherein: R¹⁰ is independently selected from F, Cl, CF₃, CHF₂, and COOH;and R^(3c) is independently selected from CHF₂, CD₃, and CH₃.
 22. Themethod according to claim 16 wherein the compound is selected from thegroup consisting of:


23. The method according to claim 22, wherein the compound has thestructure:


24. The method according to claim 22, wherein the compound has thestructure:


25. The method according to claim 22, wherein the compound has thestructure:


26. The method according to claim 22, wherein the compound has thestructure:


27. The method according to claim 22, wherein the compound has thestructure:


28. The method according to claim 22, wherein the compound has thestructure:

or a stereoisomer, a tautomer, a pharmaceutically acceptable saltthereof.
 29. The method according to claim 22, wherein the compound hasthe structure:


30. The method according to claim 22, wherein the compound has thestructure:


31. The method according to claim 22, wherein the compound has thestructure:


32. The method according to claim 22, wherein the compound has thestructure: